Fused purine derivatives

ABSTRACT

A condensed purine derivative represented by Formula (I):  
                 
 
     wherein X—Y—Z represents R 1 N—C═O or N═C—W, R 2  represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group or the like, n represents an integer of from 0 to 3, V 1  represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, V 2  represents a substituted lower alkyl group or a substituted or unsubstituted aromatic heterocyclic group, and when V 1  represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group, and for example, X—Y—Z represents R 1a N—C═O and R 2  represents a substituted lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a halogen atom, a lower alkylthio group, —NR 7 R 8 , —CO 2 H, a lower alkoxycarbonyl group, —COHal, —CONR 9 R 10  or —CHO, V 2  may represent a lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; or a pharmacologically acceptable salt thereof.

TECHNICAL FIELD

[0001] The present invention relates to condensed purine derivativeswhich have glucose concentration-dependent insulin secretion promotingaction and suitable hypoglycemic action and is useful as an antidiabeticagent.

BACKGROUND ART

[0002] Diabetes is caused by metabolic abnormality mainly ofglycometabolism, resulting from insufficient insulin secretion,decreased sensitivity of target cells of insulin and so forth, andprincipally characterized by noticeable hyperglycemia. If thehyperglycemia continues for a long period of time, serious complicationsarise in various organs and nerves such as retinopathy, nephropathy andneuropathy, which are caused mainly by vascular lesion. Therefore, forthe treatment of diabetes, it is extremely important to control andmaintain blood glucose level at a normal level, and methods for thatpurpose have been studied since old days.

[0003] For a type of diabetes where onset is gradual and insulin therapyis not necessarily required for life support (non-insulin dependentdiabetes: NIDDM), blood glucose level can be controlled by combinationof exercise therapy and drug therapy. As the drugs, insulin secretionpromoters, one of orally available hypoglycemic agents, have widely beenused clinically. However, since currently available insulin secretionpromoters all promote insulin secretion non-dependently on glucoselevel, they cause problems of severe hypoglycemia or insufficientcontrol of blood glucose if doses are not appropriate, and are not fullysatisfactory drugs. If a hypoglycemic agent can be provided that iscapable of promoting insulin secretion dependently on a blood glucoselevel, the agent is expected to be extremely useful for blood glucosecontrol of patients suffering from diabetes because the risk ofhypoglycemia due to an excess dosage can be avoided.

[0004] As condensed purine derivatives, Japanese Patent UnexaminedPublication (Kokai) No. 3-204880, Journal of Medicinal Chemistry (J.Med. Chem.), 35, p.3578, 1992, Journal of Medicinal Chemistry (J. Med.Chem.), 36, 2508, 1993, International Patent Publications WO98/15555 andWO00/57651 disclose that the compounds represented by the followingformula (A) have diuretic action, mild antiasthmatic action,antidemential action, bronchodilatation action, antiallergic action,antiulcer action, or hypoglycemic action.

[0005] wherein R^(1A) represents a hydrogen atom, a lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, R^(2A) represents a hydrogen atom, a lower alkylgroup, a substituted or unsubstituted aryl group, or a substituted orunsubstituted aromatic heterocyclic group, R^(3A) represents a hydrogenatom, a lower alkyl group, or a substituted or unsubstituted aralkylgroup, V^(1A) and V^(2A) may be the same or different and eachrepresents a hydrogen atom, a lower alkyl group, a substituted orunsubstituted aralkyl group, or a substituted or unsubstituted arylgroup, and m represents an integer of from 0 to 3.

[0006] Journal of Medicinal Chemistry (J. Med. Chem.), 23, 1188, 1980discloses that the compound represented by the following formula (B) hasmild bronchodilatation action.

[0007] Journal of Medicinal Chemistry (J. Med. Chem.), 40, 3248, 1997and Japanese Patent Unexamined Publication No. 10-158267 disclose thatthe compounds represented by the following formula (C) have type IVphosphodiesterase inhibitory action (bronchodilatation action).

[0008] wherein R^(1C), R^(3C) and R^(4C) may be the same or differentand each represents a hydrogen atom or a C₁-C₆ alkyl group which may besubstituted with a lower alkyloxy group or an acyl group, and prepresents an integer of from 1 to 4.

[0009] Furthermore, EP390111A discloses that the compounds representedby the following formula (D) have adenosine antagonizing action.

[0010] wherein R^(4D) represents a hydrogen atom, a phenyl group, orβ-D-ribofuranosyl group, WD represents a hydrogen atom, an alkyl grouphaving 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbonatoms, V^(1D) represents an aralkyl group, V^(2D) represents a hydrogenatom or a phenyl group, and when V^(2D) is a phenyl group, V^(1D) mayrepresent an alkyl group having 1 to 6 carbon atoms.

DISCLOSURE OF THE INVENTION

[0011] An object of the present invention is to provide a medicamentuseful for prophylactic and/or therapeutic treatment of diabetes orcomplications of diabetes. More specifically, the object is to provide amedicament that has a blood sugar level-dependent insulin secretionpromoting action.

[0012] The inventors of the present invention conducted variousresearches to achieve the aforementioned object. As a result, they foundthat the compounds represented by the following formula (I) had aninsulin secretion promoting action and were useful as an activeingredient of antidiabetic agents. The present invention was achieved onthe basis of the aforementioned finding.

[0013] The present invention thus relates to the following subjectmatters (1) to (23).

[0014] (1) A condensed purine derivative represented by Formula (I):

[0015] wherein X—Y—Z represents R¹N—C═O (in the formula, R¹ represents ahydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group) or N═C—W [in the formula, W represents a halogenatom, a substituted or unsubstituted aromatic heterocyclic group, asubstituted or unsubstituted alicyclic heterocyclic group, —NR⁴R⁵ (inthe formula, R⁴ and R⁵ may be the same or different and each representsa hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aryl group, or a substituted orunsubstituted aralkyl group, or R⁴ and R⁵ may bind to each other to forma heterocyclic group together with the adjacent nitrogen atom), —OR⁶ (inthe formula, R⁶ represents a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted aryl group, or a substituted orunsubstituted aralkyl group), —SR^(6a) (in the formula, R^(6a) has thesame meaning as R⁶ mentioned above), a substituted or unsubstitutedlower alkyl group or a cyano group], R² represents a hydrogen atom, asubstituted or unsubstituted lower alkyl group, a substituted orunsubstituted aralkyl group, a substituted or unsubstituted aryl group,a substituted or unsubstituted aromatic heterocyclic group, asubstituted or unsubstituted alicyclic heterocyclic group, a halogenatom, a lower alkylthio group, —NR⁷R⁸ (in the formula, R⁷ and R⁸ havethe same meanings as R⁴ and R⁵ mentioned above, respectively), —CO₂H, alower alkoxycarbonyl group, —COHal (in the formula, Hal represents ahalogen atom), —CONR⁹R¹⁰ (in the formula, R⁹ and R¹⁰ have the samemeanings as R⁴ and R⁵ mentioned above, respectively) or —CHO, R³represents a hydrogen atom, a lower alkyl group, a substituted orunsubstituted aralkyl group, or a lower alkoxyalkyl group, n representsan integer of from 0 to 3, V¹ represents a hydrogen atom, a substitutedor unsubstituted lower alkyl group, a substituted or unsubstitutedaralkyl group, a substituted or unsubstituted aryl group, or asubstituted or unsubstituted aromatic heterocyclic group, V² representsa substituted lower alkyl group, or a substituted or unsubstitutedaromatic heterocyclic group, and

[0016] when V¹ represents a hydrogen atom, a lower alkyl group, asubstituted or unsubstituted aralkyl group, or a substituted orunsubstituted aryl group, and (a) X—Y—Z represents R^(1a)N—C═O (in theformula, R^(1a) represents any of the groups in the definition of theaforementioned R¹ excluding a substituted lower alkyl group), and R²represents a substituted lower alkyl group, a substituted orunsubstituted aralkyl group, a substituted or unsubstituted alicyclicheterocyclic group, a halogen atom, a lower alkylthio group, —NR⁷R⁸ (inthe formula, R⁷ and R⁸ have the same meanings as defined above,respectively), —CO₂H, a lower alkoxycarbonyl group, —COHal (in theformula, Hal has the same meaning as defined above), —CONR⁹R¹⁰ (in theformula, R⁹ and R¹⁰ have the same meanings as those defined above,respectively) or —CHO, (b) X—Y—Z represents R¹N—C═O (in the formula, R¹has the same meaning as defined above), and R³ represents a loweralkoxyalkyl group, (c) X—Y—Z represents R^(1b)N—C═O (in the formula,R^(1b) represents a substituted lower alkyl group), (d) X—Y—Z representsN═C—W (in the formula, W has the same meaning as defined above), and R²represents a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted aromaticheterocyclic group, a substituted or unsubstituted alicyclicheterocyclic group, a halogen atom, a lower alkylthio group, —NR⁷R⁸ (inthe formula, R⁷ and R⁸ have the same meanings as defined above,respectively), —CO₂H, a lower alkoxycarbonyl group, —COHal (in theformula, Hal has the same meaning as defined above), —CONR⁹R¹⁰ (in theformula, R⁹ and R¹⁰ have the same meanings as defined above,respectively) or —CHO, or (e) X—Y—Z represents N═C—W (in the formula, Whas the same meaning as defined above), and R³ represents a lower alkylgroup, a substituted or unsubstituted aralkyl group, or a loweralkoxyalkyl group, V² may represent a lower alkyl group, a substitutedor unsubstituted aralkyl group, or a substituted or unsubstituted arylgroup; or a pharmacologically acceptable salt thereof.

[0017] (2) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (1), whereinX—Y—Z represents R¹N—C═O (in the formula, R¹ has the same meaning asdefined above).

[0018] (3) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (2), wherein R¹and R² represent a substituted or unsubstituted lower alkyl group and R³represents a hydrogen atom.

[0019] (4) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (2) or (3),wherein at least one of V¹ and V² represents a substituted lower alkylgroup.

[0020] (5) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (2) or (3),wherein at least one of V¹ and V² represents a substituted orunsubstituted aralkyl group.

[0021] (6) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (1), whereinX—Y—Z represents N═C—W (in the formula, W has the same meaning asdefined above).

[0022] (7) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (6), wherein R²represents a substituted or unsubstituted lower alkyl group.

[0023] (8) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to the aforementioned (6) or (7),wherein at least one of V¹ and V² represents a substituted orunsubstituted aralkyl.

[0024] (9) The condensed purine derivative or a pharmacologicallyacceptable salt thereof according to any one of the aforementioned (1)to (8), wherein n is 0.

[0025] (10) A pharmaceutical composition which comprises the condensedpurine derivative or a pharmacologically acceptable salt thereofaccording to any one of the aforementioned (1) to (9) as an activeingredient.

[0026] (11) An agent for prophylactic and/or therapeutic treatment ofdiabetes, which comprises the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) as an active ingredient.

[0027] (12) An agent for prophylactic and/or therapeutic treatment of acomplication of diabetes, which comprises the condensed purinederivative or a pharmacologically acceptable salt thereof according toany one of the aforementioned (1) to (9) as an active ingredient.

[0028] (13) A hypoglycemic agent which comprises the condensed purinederivative or a pharmacologically acceptable salt thereof according toany one of the aforementioned (1) to (9) as an active ingredient.

[0029] (14) An insulin secretion promoter which comprises the condensedpurine derivative or a pharmacologically acceptable salt thereofaccording to any one of the aforementioned (1) to (9) as an activeingredient.

[0030] (15) Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) for the manufacture of a pharmaceuticalcomposition.

[0031] (16) Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) for the manufacture of an agent forprophylactic and/or therapeutic treatment of diabetes.

[0032] (17) Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) for the manufacture of an agent forprophylactic and/or therapeutic treatment of a complication of diabetes.

[0033] (18) Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) for the manufacture of a hypoglycemic agent.

[0034] (19) Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9) for the manufacture of an insulin secretionpromoter.

[0035] (20) A method for prophylactic and/or therapeutic treatment ofdiabetes, which comprises a step of administering an effective amount ofthe condensed purine derivative or a pharmacologically acceptable saltthereof according to any one of the aforementioned (1) to (9).

[0036] (21) A method for prophylactic and/or therapeutic treatment of acomplication of diabetes, which comprises a step of administering aneffective amount of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of theaforementioned (1) to (9).

[0037] (22) A method for decreasing blood sugar level, which comprises astep of administering an effective amount of the condensed purinederivative or a pharmacologically acceptable salt thereof according toany one of the aforementioned (1) to (9).

[0038] (23) A method for promoting insulin secretion, which comprises astep of administering an effective amount of the condensed purinederivative or a pharmacologically acceptable salt thereof according toany one of the aforementioned (1) to (9).

[0039] The aforementioned medicaments are preferably provided in theform of a pharmaceutical composition comprising a condensed purinederivative represented by Formula (I) or a pharmacologically acceptablesalt thereof and one or more additives for pharmaceutical preparations.

[0040] Hereinafter, the compounds represented by Formula (I) arereferred to as Compound (I). The same shall apply to the compounds ofthe other formula numbers.

[0041] In the definition of each group in Formula (I), a lower alkylmoiety of a lower alkyl group, a lower alkylthio group, a loweralkoxycarbonyl group, and a lower alkoxyalkyl group includes a straight,branched, and cyclic alkyl groups as well as a combination thereof,which have about 1 to 10 carbon atoms. The cyclic lower alkyl may haveone or more rings. Examples of the straight or branched lower alkylgroup include, for example, a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a n-pentyl group, a neopentylgroup, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonylgroup, a n-decyl group and the like. Examples of the cyclic lower alkylinclude, for example, a cyclopropyl group, a cyclopropylmethyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptylgroup, a cyclooctyl group, a 1-methylcyclohexyl group, a4-methylcyclohexyl group, a noradamantyl group, an adamantyl group, abicyclo[2.2.1]heptyl group, a bicyclo[2.2.2]octyl group, abicyclo[3.3.0]octyl group, a bicyclo[3.3.1]nonyl group and the like.

[0042] An alkylene moiety of the lower alkoxyalkyl group and the aralkylgroup corresponds to that obtained by eliminating one hydrogen atom fromthe straight or branched lower alkyl mentioned above.

[0043] An aryl moiety of the aryl group and the aralkyl group consistsof a monocyclic ring or two or more condensed rings. Examples thereofinclude those having about 6 to 14 ring-constituting carbon atoms, forexample, a phenyl group, a naphthyl group, an indenyl group, ananthranyl group and the like.

[0044] Examples of the aromatic heterocyclic group include, for example,5- or 6-membered monocyclic aromatic heterocyclic groups containing atleast one atom selected from a nitrogen atom, an oxygen atom, and asulfur atom, bicyclic or a tricyclic condensed aromatic heterocyclicgroups comprising 3- to 8-membered rings and containing at least oneatom selected from a nitrogen atom, an oxygen atom, and a sulfur atomand the like. More specific examples include those having 5 to 14ring-constituting atoms such as a furyl group, a thienyl group, apyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolylgroup, a tetrazolyl group, an oxazolyl group, a thiazolyl group, apyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinylgroup, a triazinyl group, an indolyl group, an indazolyl group, abenzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, aquinolyl group, an isoquinolyl group, a phthalazinyl group, anaphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, acinnolinyl group, a purinyl group and the like.

[0045] Examples of the alicyclic heterocyclic group include, forexample, 5- or 6-membered monocyclic alicyclic heterocyclic groupscontaining at least one atom selected from a nitrogen atom, an oxygenatom, and a sulfur atom, bicyclic or tricyclic condensed alicyclicheterocyclic groups comprising 3- to 8-membered rings and containing atleast one atom selected from a nitrogen atom, an oxygen atom, and asulfur atom. More specific examples include a pyrrolidinyl group, a2,5-dioxopyrrolidinyl group, a thiazolidinyl group, an oxazolidinylgroup, a 2-oxooxazolidinyl group, a piperidinyl group, a piperazinylgroup, a homopiperazinyl group, a morpholinyl group, a thiomorpholinylgroup, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, atetrahydrofuryl group, a tetrahydroquinolyl group, atetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, anoctahydroquinolyl group, a dihydroindolyl group, a 1,3-dioxoisoindolinylgroup, a 1,3-dioxolanyl group, a 1,3-dioxolane-2-spirocyclopentyl groupand the like.

[0046] Examples of the heterocyclic group formed together with theadjacent nitrogen atom include, for example, 5- or 6-membered monocyclicheterocyclic groups containing at least one nitrogen atom (saidmonocyclic heterocyclic group may contain a nitrogen atom other than theabove, an oxygen atom, or a sulfur atom), bicyclic or tricycliccondensed heterocyclic groups comprising 3- to 8-membered rings andcontaining at least one nitrogen atom (said condensed heterocyclic groupmay contain a nitrogen atom other than the above, an oxygen atom, or asulfur atom). More specific examples include a pyrrolidinyl group, athiazolidinyl group, an oxazolidinyl group, a piperidino group, ahomopiperidino group, a piperazinyl group, a homopiperazinyl group, amorpholino group, a thiomorpholino group, a tetrahydroquinolyl group, atetrahydroisoquinolyl group, an octahydroquinolyl group, abenzimidazolyl group, an indazolyl group, an indolyl group, anisoindolyl group, a purinyl group, a dihydroindolyl group, a pyrrolylgroup, a pyrazolyl group, a triazolyl group, a tetrazolyl group, animidazolyl group and the like.

[0047] Examples of the halogen atom include a fluorine atom, a chlorineatom, a bromine atom and an iodine atom.

[0048] Examples of substituents of the substituted aryl group, thesubstituted aralkyl group, the substituted aromatic heterocyclic group,and the substituted alicyclic heterocyclic group, which may be the sameor different and in number of 1 to 3, include a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted aryloxy group, a substituted orunsubstituted aroyl group, a substituted or unsubstituted aralkyl group,a substituted or unsubstituted aralkyloxy group, a substituted orunsubstituted lower alkenyl group, a substituted or unsubstituted loweralkynyl group, a substituted or unsubstituted lower alkoxy group, asubstituted or unsubstituted lower alkoxycarbonyl group, a substitutedor unsubstituted lower alkylthio group, a substituted or unsubstitutedlower alkylsulfonyl group, a substituted or unsubstituted lower alkanoylgroup, a mono- or di-lower alkyl-substituted carbamoyl group, a mono- ordi-lower alkyl-substituted amino group, a halogen atom, a carboxylgroup, a hydroxyl group, a nitro group, an amino group, a cyano groupand the like. Examples of the lower alkenyl group used herein include astraight and branched alkenyl groups having 2 to 6 carbon atoms such asa vinyl group, an allyl group, a 1-propenyl group, a methacryl group, abutenyl group, a crotyl group, a pentenyl group, and a hexenyl group,and examples of the lower alkynyl group used herein include a straightand branched alkynyl groups having 2 to 6 carbon atoms such as anethynyl group, a propynyl group, a butynyl group, a pentynyl group, anda hexynyl group. Numbers of unsaturated bond in the lower alkenyl groupand the lower alkynyl group are not particularly limited, and theypreferably contain one unsaturated bond. Each lower alkyl moiety of thelower alkyl group, the lower alkoxy group, the lower alkoxycarbonylgroup, the lower alkylthio group, the lower alkylsulfonyl group, thelower alkanoyl group, the mono- or di-lower alkyl-substituted carbamoylgroup, and the mono- or di-lower alkyl-substituted amino group has thesame meaning as the aforementioned lower alkyl group. Each alkylenemoiety of the aralkyl group and the aralkyloxy group has the samemeaning as the aforementioned alkylene moiety. Each aryl moiety of thearyl group, the aryloxy group, and the aroyl group has the same meaningas the aforementioned aryl group. The halogen atom has the same meaningas the aforementioned halogen atom. Examples of substituents of thesubstituted lower alkyl group, the substituted aryl group, thesubstituted aryloxy group, the substituted aroyl group, the substitutedaralkyl group, the substituted aralkyloxy group, the substituted loweralkenyl group, the substituted lower alkynyl group, the substitutedlower alkoxy group, the substituted lower alkoxycarbonyl group, thesubstituted lower alkylthio group, the substituted lower alkylsulfonylgroup, and the substituted lower alkanoyl group, which may be the sameor different and in number of 1 to 3, include a hydroxyl group, ahalogen atom having the same meaning as defined above, a carboxyl group,a sulfo group, a phosphono group, an ester derived from any of theseacidic groups (e.g., a lower alkyl ester, an aralkyl ester, an arylester and the like: the lower alkyl moiety, the aralkyl moiety, and thearyl moiety of these esters have the same meanings as those definedabove, respectively). In the di-lower alkyl-substituted carbamoyl groupand the di-lower alkyl-substituted amino group, two of the lower alkylgroups which bind to a carbamoyl group or an amino group may be the sameor different.

[0049] Examples of substituents of the substituted lower alkyl, whichmay be the same or different and in number of 1 to 3, include a loweralkoxy group, a hydroxyl group, a cyano group, an azido group, acarboxyl group, a phosphono group, an ester group derived from any ofthese acidic groups (e.g., a lower alkyl ester, an aralkyl ester, anaryl ester and the like: the lower alkyl moiety, the aralkyl moiety, andthe aryl moiety of these esters have the same meanings as those definedabove, respectively), a lower alkylthio group, a loweralkylaminocarbonyl group, a lower alkoxycarbonyl group, a substituted orunsubstituted aromatic heterocyclic group, a substituted orunsubstituted alicyclic heterocyclic group, —NR¹¹R¹² (in the formula,R¹¹ and R¹² may be the same or different and each represents a hydrogenatom, a lower alkyl group, a lower alkanoyl group, an aryl group, anaralkyl group, or an aralkyloxy group, or R¹¹ and R¹² may bind to eachother to form a heterocyclic group together with the adjacent nitrogenatom), a halogen atom, an arylsulfonyloxy group which may be substitutedwith a lower alkyl group, a lower alkylsulfonyl group, a loweralkylsulfonyloxy group, a trifluoromethanesulfonyloxy group and thelike. Each lower alkyl moiety of the lower alkyl group, the lower alkoxygroup, the lower alkylthio group, the lower alkylaminocarbonyl group,the lower alkoxycarbonyl group, the lower alkanoyl group, thearylsulfonyloxy group which may be substituted with a lower alkyl group,the lower alkylsulfonyl group, and the lower alkylsulfonyloxy group hasthe same meaning as the aforementioned lower alkyl group. Each arylmoiety of the aryl group, the aralkyl group, the aralkyloxy group, andthe arylsulfonyloxy group has the same meaning as the aforementionedaryl group. An alkylene moiety of the aralkyl has the same meaning asthe aforementioned alkylene moiety. The halogen atom, the aromaticheterocyclic group, the alicyclic heterocyclic group, and theheterocyclic group formed together with the adjacent nitrogen atom havethe same meanings as defined above, respectively. Substituents of thesubstituted aromatic heterocyclic group and the substituted alicyclicheterocyclic group have the same meanings as those mentioned above.

[0050] Further, in Formula (I), the substituting position of V¹ or V² isnot particularly limited, and each of them may substitute at anyposition on the ring. When V¹ or V² is a substituent other than ahydrogen atom, the stereochemistry of the carbon atom to which it bindsmay be either in S- or R-configuration. Symbol “n” is preferably 0.

[0051] Examples of pharmacologically acceptable salts of Compound (I)include acid addition salts such as inorganic acid salts and organicacid salts, base addition salts such as metal salts, ammonium salts, andorganic ammonium salts, amino acid addition salts and the like. Examplesof the pharmacologically acceptable acid addition salts include, forexample, inorganic acid salts such as hydrochlorides, sulfates, andphosphates, organic acid salts such as acetates, maleates, fumarates,tartrates, and citrates. Examples of the pharmacologically acceptablemetal salts include, for example, alkali metal salts such as sodiumsalts and potassium salts, alkaline earth metal salts such as magnesiumsalts and calcium salts, as well as aluminum salts, zinc salts and thelike. Examples of the pharmacologically acceptable organic ammoniumsalts include, for example, addition salts of an organic amine such asmorpholine or piperidine. Examples of the pharmacologically acceptableamino acid addition salts include, for example, addition salts oflysine, glycine, phenylalanine or the like.

[0052] Compound (I) or a pharmacologically acceptable salt thereof mayexist in the form of a hydrate or a solvate, and these adducts also fallwithin the scope of the present invention. A type of a solvent thatforms the solvate is not particularly limited so long as the solvent ispharmacologically acceptable. For example, ethanol, acetone or the likecan be used. Compound (I) may sometimes have one or more asymmetriccarbons, and any of optical isomers and diastereoisomers in a pure form,any mixtures of these isomers, racemates and the like fall within thescope of the present invention. When Compound (I) contains a doublebond, the bond may be either in Z- or E-configuration. When a tautomerof Compound (I) exists, the tautomer may be in any form of tautomerismand any possible isomers and mixtures thereof fall within the scope ofthe present invention.

[0053] Methods for producing Compound (I) will be explained below.

[0054] When any defined group changes under a given reaction conditionor is not suitable for carrying out a reaction process in the schemesmentioned below, preparation may be readily carried out by applyingmethods commonly used in the filed of synthetic organic chemistry suchas protection and deprotection of a functional group [see, for example,T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,Inc. (1981) and the like].

[0055] (In the formulas, R^(2a) represents a hydrogen atom, asubstituted or unsubstituted lower alkyl group, a substituted orunsubstituted aralkyl group, a substituted or unsubstituted aryl group,or a substituted or unsubstituted aromatic heterocyclic group, and n,R¹, R³, V¹ and V² have the same meanings as those defined above,respectively. The lower alkyl group, the aralkyl group, the aryl group,the aromatic heterocyclic group, and substituents of the substitutedlower alkyl group, the substituted aralkyl group, the substituted arylgroup and the substituted aromatic heterocyclic group have the samemeanings as those defined above, respectively.)

[0056] Compound (Ia), which corresponds to Compound (I) wherein X—Y—Z isR¹N—C═O (in the formula, R¹ has the same meaning as defined above), R²is a hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, can be produced through Steps 1 and 2 describedbelow from Compound (II), which is a known compound or a compound thatcan be obtained by a method similar to the known one in a method similarto that described in International Patent Publication WO98/15555,Japanese Patent Unexamined Publication No. 3-204480, Journal ofMedicinal Chemistry (J. Med. Chem.), 35, p.3578, 1992, Journal ofMedicinal Chemistry (J. Med. Chem.), 36, p.2508, 1993, Journal ofHeterocyclic Chemistry (J. Heterocycl. Chem.), 30, p.241, 1993 or thelike. According to the methods disclosed in the above references orpreparation methods specifically described in the present specification,or with suitable changes of regents and reaction starting materials aswell as with optional modifications or alterations of the methods, thoseskilled in the art can produce Compound (I).

[0057] Step 1

[0058] Compound (IV) can be obtained by reacting Compound (II) with 1 to10 equivalents, preferably 2 to 5 equivalents, of Compound (III) withouta solvent or in a suitable solvent. Examples of the solvent include, forexample, alcohols such as methanol, ethanol, and isopropanol, aromatichydrocarbons such as toluene and xylene, halogenated hydrocarbons suchas dichloroethane, 1,1,2,2-tetrachloroethane and dichlorobenzene,pyridine, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidinone, N,N′-dimethylimidazolidin-2-one, dimethylsulfoxide and so forth, and these solvents are used each alone or as amixture thereof. The reaction is performed at a temperature between 30°C. and a boiling point of the solvent used and finishes in 5 minutes to24 hours.

[0059] Compound (IV) can also be produced by the following method.

[0060] Compound (IV) can be obtained by oxidizing Compound (II) into asulfone compound (IIa) by treating it with a mono persulfate compound orthe like in a suitable solvent, and then removing the solvent, andfurther reacting the sulfone compound with 1 to 10 equivalents,preferably 2 to 5 equivalents, of Compound (III). Examples of thesolvent for the oxidation reaction include, for example, ketones such asacetone and methyl ethyl ketone, alcohols such as methanol and ethanol,halogenated hydrocarbons such as chloroform and dichloroethane, aromatichydrocarbons such as toluene, ethyl acetate, water and so forth, andthese solvents are used each alone or as a mixture thereof. When atwo-phase system is used, the reaction may be performed by mixing aphase transfer catalyst. Examples of the phase transfer catalyst includetetrabutylammonium chloride, benzyltributylammonium chloride,tetrabutylammonium hydrogensulfate and so forth, and the reaction isperformed at a temperature between 0° C. and room temperature andfinishes in 1 to 12 hours. Examples of the solvent for the aminationinclude, for example, aromatic hydrocarbons such as toluene and xylene,halogenated hydrocarbons such as dichloroethane,1,1,2,2-tetrachloroethane and dichlorobenzene, pyridine,N,N-dimethylformamide,

[0061] N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone,N,N′-dimethylimidazolidin-2-one, dimethyl sulfoxide and so forth, andthese solvents are used each alone or as a mixture thereof. The reactionis performed at a temperature between room temperature and a boilingpoint of the solvent used and finishes in 1 to 24 hours.

[0062] Compound (II) as a starting material can be obtained according toa known method [Journal of Chemical Society Perkin I (J. Chem. Soc.Perkin I), p.739, 1973 or Journal of Heterocyclic Chemistry (J.Heterocycl. Chem.), 30, p.241, 1993] or a similar method thereto.

[0063] Compound (III) as a starting material can be obtained by, forexample, treating a known amino acid derivative with 1 to 10equivalents, preferably 2 to 5 equivalents, of a reducing agent, forexample, a metal hydrogen complex compound such as lithium aluminumhydride, sodium borohydride or lithium borohydride, diborane or the likein a suitable solvent. Examples of the solvent include, for example,diethyl ether, tetrahydrofuran, diethylene glycol dimethyl ether and soforth. The reaction is performed at a temperature between 0° C. and aboiling point of the solvent used and finishes in 30 minutes to 24hours. When the amino group of the starting amino acid derivative isprotected, its deprotection can be carried out by using a method usuallyused in the filed of synthetic organic chemistry.

[0064] Step 2

[0065] Compound (Ia) can be obtained by treatment of Compound (IV) with1 equivalent to large excess, preferably large excess, of a halogenatingagent such as thionyl chloride or phosphorus oxychloride, or with aninorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodicacid or phosphoric acid, or alternatively, with 1 to 5 equivalents,preferably 1 to 2 equivalents, of a sulfonylating agent such asbenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonylchloride or trifluoromethanesulfonyl chloride in the presence of 1 to 10equivalents, preferably 1 to 5 equivalents, of an organic base such astriethylamine, diisopropylethylamine or pyridine or an inorganic basesuch as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogen carbonate, potassium hydroxide, or sodiumhydroxide, without a solvent or in a suitable solvent. Examples of thesolvent include, for example, halogenated hydrocarbons such as methylenechloride, chloroform and dichloroethane, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide and so forth, and thesesolvents are used each alone or as a mixture thereof. The reaction isperformed at a temperature between −10° C. and 150° C., preferably at atemperature between 50° C. and 70° C., and finishes in 5 minutes to 24hours.

[0066] (In the formulas, R^(3a) represents a lower alkyl group or asubstituted or unsubstituted aralkyl group, W¹ represents a halogenatom, and n, R^(2a), V¹, and V² have the same meanings as those definedabove, respectively. The lower alkyl group, the aralkyl group, thehalogen atom, and the substituents of the substituted aralkyl group havethe same meanings as those defined above, respectively.)

[0067] Compound (Ib), which corresponds to Compound (I) wherein X—Y—Z isN═C—W¹ (in the formula, W¹ has the same meaning as defined above), R² isa hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, and R³ is a lower alkyl group or a substituted orunsubstituted aralkyl group, can be produced through Steps 3 to 5 fromCompound (V) which can be obtained by a known method (Japanese PatentUnexamined Publication No. 8-500344) or a similar method thereto.

[0068] Step 3

[0069] Compound (VI) can be obtained by treatment of Compound (V) with 1equivalent to large excess, preferably large excess, of a halogenatingagent, used alone or in combination, such as phosphorus pentachloride orphosphorus oxychloride without a solvent or in a suitable solvent,optionally with addition of 1 to 10 equivalents, preferably 1 to 3equivalents, of a tertiary amine such as triethylamine ordiisopropylethylamine. Examples of the solvent include, for example,halogenated hydrocarbons such as chloroform and dichloroethane. Thereaction is performed at a temperature between 70° C. and 150° C.,preferably at a temperature between 100° C. and 130° C., and finishes in1 to 24 hours.

[0070] Step 4

[0071] Compound (VII) can be obtained by reacting Compound (VI) with 2to 20 equivalents, preferably 2 to 5 equivalents, of Compound (III) in asuitable solvent, optionally in the presence of 1 to 10 equivalents,preferably 1 to 3 equivalents, of a tertiary amine such as triethylamineor diisopropylethylamine or an inorganic base such as sodium carbonate,cesium carbonate, or sodium hydrogen carbonate. Examples of the solventinclude, for example, N,N-dimethylformamide, dimethyl sulfoxide,1-methyl-2-pyrrolidinone, acetonitrile and so forth, and these solventsare used each alone or as a mixture thereof. The reaction is performedat a temperature between 0° C. and a boiling point of the solvent used,preferably at a temperature between 0° C. and room temperature, andfinishes in 1 to 24 hours, preferably in 1 to 5 hours.

[0072] Step 5

[0073] Compound (Ib) can be produced from Compound (VII) in a mannersimilar to that of Step 2.

[0074] (In the formulas, R^(3b) represents a hydrogen atom, a loweralkyl group, or a substituted or unsubstituted aralkyl group, R¹³represents a lower alkyl group, and n, R^(2a), V¹, V², and W¹ have thesame meanings as those defined above, respectively. The lower alkylgroup, the aralkyl group, and the substituents of the substitutedaralkyl group have the same meanings as those defined above,respectively.)

[0075] Compound (Ic), which corresponds to Compound (I) wherein X—Y—Z isN═C—W¹ (in the formula, W¹ has the same meaning as defined above), R² isa hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, and R³ is a hydrogen atom, a lower alkyl group, or asubstituted or unsubstituted aralkyl group, can be produced throughSteps 6 to 9.

[0076] Step 6

[0077] Compound (IX) can be produced from Compound (VIII) in a mannersimilar to that of Step 3.

[0078] Step 7

[0079] Compound (X) can be obtained by reacting Compound (IX) with 1 to10 equivalents, preferably 2 to 5 equivalents, of Compound (III) in asuitable solvent, optionally in the presence of 1 to 10 equivalents,preferably 1 to 3 equivalents, of a tertiary amine such as triethylamineor diisopropylethylamine or inorganic base such as sodium carbonate,cesium carbonate or sodium hydrogen carbonate. Examples of the solventinclude, for example, alcohols such as n-propanol, isopropanol andn-butanol, aromatic hydrocarbons such as toluene and xylene, halogenatedhydrocarbons such as dichloroethane, 1,1,2,2-tetrachloroethane anddichlorobenzene, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidinone, N,N′-dimethylimidazolidin-2-one, dimethylsulfoxide and so forth, and these solvents are used each alone or as amixture thereof. The reaction is performed at a temperature between 80°C. and 150° C. and finishes in 2 to 12 hours.

[0080] Step 8

[0081] Compound (XI) can be obtained by oxidizing Compound (X) with 1 to10 equivalents, preferably 2 to 5 equivalents, of a monopersulfatecompound in a suitable solvent, optionally in the presence of 0.1 to 0.5equivalent of a phase transfer catalyst such as tetrabutylammoniumchloride, benzyltributylammonium chloride or tetrabutylammoniumhydrogensulfate. Examples of the solvent include, for example, ketonessuch as acetone and methyl ethyl ketone, alcohols such as methanol andethanol, water and so forth, and these solvents are used each alone oras a mixture thereof. The reaction is performed at a temperature between0° C. and room temperature and finishes in 1 to 12 hours.

[0082] Step 9

[0083] Compound (Ic) can be produced from Compound (XI) in a mannersimilar to that of Step 2.

[0084] Further, Compound (Ic) obtained by the aforementioned preparationmethod can also be used as a synthetic intermediate and converted intoanother Compound (I).

[0085] (In the formulas, A represents a lower alkylene group, Brepresents a suitable leaving group such as a halogen atom, amethanesulfonyloxy group, a toluenesulfonyloxy group, or atrifluoromethanesulfonyloxy group, q represents 1 or 2, and n, R¹,R^(2a), R³, R¹¹ and R¹² have the same meanings as those defined above,respectively. The lower alkylene group has the same meaning as theaforementioned alkylene moiety, and the halogen atom has the samemeaning as defined above. When q is 2, two of A-B or A-NR¹¹R¹² may bethe same or different, and the same shall apply to the followingdescription.)

[0086] Step 10

[0087] Compound (Iaa), which corresponds to Compound (Ia) wherein V¹ orV² is a lower alkyl group substituted with —NR¹¹R¹² (in the formula, R¹¹and R¹² have the same meanings as defined above, respectively), can beobtained by reacting Compound (Iab), which corresponds to Compound (Ia)wherein V¹ or V² is a substituted lower alkyl group having a suitableleaving group such as a halogen atom, a methanesulfonyloxy group, atoluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group, with 2to 20 equivalents, preferably 5 to 10 equivalents, of HNR¹¹R¹² in asuitable solvent, optionally in the presence of 1 to 10 equivalents,preferably 1 to 3 equivalents, of a tertiary amine such as triethylamineor diisopropylethylamine or an inorganic base such as sodium carbonate,cesium carbonate or sodium hydrogen carbonate. Examples of the solventinclude, for example, water, alcohols such as methanol and ethanol,halogenated hydrocarbons such as methylene chloride, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and so forth,and these solvents are used each alone or as a mixture thereof. Thereaction is performed at a temperature between 0° C. and a boiling pointof the solvent used, preferably at a temperature between 0° C. and roomtemperature, and finishes in 1 to 24 hours, preferably in 1 to 5 hours.

[0088] Further, Compound (Iaa1), which corresponds to Compound (Iaa)wherein each of R¹¹ and R¹² represents a hydrogen atom, can also beproduced by the method described below.

[0089] (In the formulas, A, B, n, q, R¹, R^(2a) and R³ have the samemeanings as those defined above, respectively.)

[0090] Step 11

[0091] Compound (Iab) can be reacted with 1 to 5 equivalents of asuitable azidating agent such as sodium azide, potassium azide, lithiumazide, or trimethylsilyl azide in a suitable solvent to obtaincorresponding Azide compound (Iac). Examples of the solvent include, forexample, water, alcohols such as methanol and ethanol, tetrahydrofuran,diethylene glycol dimethyl ether, N,N-dimethylformamide and so forth,and these solvents are used each alone or as a mixture thereof. Thereaction is performed at a temperature between 0° C. and 160° C.,preferably at a temperature between room temperature and 100° C., andfinishes in 1 to 72 hours, preferably in 1 to 24 hours.

[0092] (In the formulas, A, n, q, R¹, R^(2a) and R³ have the samemeanings as those defined above, respectively.)

[0093] Step 12

[0094] Compound (Iaa1) can be obtained by reducing Azide Compound (Iac)obtained in Step 11 in a suitable solvent under ordinary pressure orpositive pressure of hydrogen flow in the presence of a catalyst such aspalladium, nickel or platinum, optionally in the presence of aninorganic base such as calcium carbonate. Examples of the solventinclude, for example, alcohols such as methanol and ethanol,tetrahydrofuran and so forth, and these solvents are used each alone oras a mixture thereof. The reaction is performed at a temperature betweenroom temperature and a boiling point of the solvent used and finishes in1 to 24 hours, preferably in 1 to 6 hours.

[0095] Compound (Iaa1) can also be obtained by treating Azide Compound(Iac) mentioned above in a solvent such as water, methanol, ethanol,toluene, or diethyl ether in the presence of a reducing agent such assodium borohydride, lithium aluminum hydride, borane, ortriphenylphosphine at a temperature between 0° C. and a boiling point ofthe solvent used for 1 to 24 hours, preferably for 1 to 6 hours.

[0096] Furthermore, Compound (Iaa1) can also be produced by the methoddescribed below.

[0097] (In the formulas, A, B, n, q, R¹, R^(2a) and R³ have the samemeanings as those defined above, respectively.)

[0098] Step 13

[0099] Compound (lab) can be reacted with 1 to 5 equivalents ofphthalimide potassium salt in a suitable solvent to obtain acorresponding N-substituted phthalimide compound. Examples of thesolvent include tetrahydrofuran, diethylene glycol dimetyl ether,N,N-dimethylformamide and so forth, and these solvents are used eachalone or as a mixture thereof. The reaction is performed at atemperature between 0° C. and 160° C., preferably at a temperaturebetween room temperature and 120° C., and finishes in 1 to 72 hours,preferably in 1 to 6 hours. Subsequently, the obtained N-substitutedphthalimide compound can be hydrolyzed with an acid by usinghydrochloric acid, sulfuric acid or the like, or reacted with largeexcess of hydrazine in a suitable solvent to obtain Compound (Iaa1).Examples of the solvent include, for example, chloroform, methanol,ethanol, tetrahydrofuran and so forth, and these solvents are used eachalone or as a mixture thereof. The reaction is performed at atemperature between room temperature and a boiling point of the solventused and finishes in 1 to 24 hours, preferably in 1 to 12 hours.

[0100] Compound (Iaa2), which corresponds to Compound (Iaa) wherein R¹¹and R¹² form a heterocyclic group together with the adjacent nitrogenatom can also be produced by the method described below.

[0101] (In the formulas, D represents a heterocyclic group formedtogether with the adjacent nitrogen atom, and A, B, n, q, R¹, R^(2a) andR³ have the same meanings as those defined above, respectively. Theheterocyclic group formed together with the adjacent nitrogen atom hasthe same meaning as defined above.)

[0102] Step 14

[0103] Compound (Iaa2) can also be obtained by reacting Compound (lab)with a corresponding heterocyclic compound in a suitable solvent in thepresence of an inorganic base such as potassium carbonate, sodiumcarbonate, or cesium carbonate, or with a metal salt of a correspondingheterocyclic compound, which is prepared by using a metal hydride suchas sodium hydride or potassium hydride or a metal lower alkoxide such assodium methoxide, sodium ethoxide, or potassium tert-butoxide. Examplesof the solvent include ethers such as 1,4-dioxane and tetrahydrofuran,alcohols such as methanol and ethanol, N,N-dimethylformamide, dimethylsulfoxide and so forth, and these solvents are used each alone or as amixture thereof. The reaction is performed at a temperature between 0°C. and a boiling point of the solvent used and finishes in 1 to 24hours, preferably in 1 to 6 hours.

[0104] Compound (Iaa2) can also be produced by converting an amino groupof Compound (Iaa1) into a heterocyclic group formed together with theadjacent nitrogen atom.

[0105] Preparation Method 5:

[0106] [In the formulas, R^(3c) represents a lower alkyl group, asubstituted or unsubstituted aralkyl group, or a lower alkoxyalkylgroup, X¹—Y¹—Z¹ represents R¹N—C═O (in the formula, R¹ has the samemeaning as defined above) or N═C—W² (in the formula, W² represents agroup defined for the aforementioned W excluding a halogen atom, B¹ hasthe same meaning as the aforementioned B, and n, R⁷, R⁸, V¹ and V² havethe same meanings as those defined above, respectively. The lower alkylgroup, the aralkyl group, the lower alkoxyalkyl group, the halogen atom,and the substituents of the substituted aralkyl group have the samemeanings as those defined above, respectively.)

[0107] Step 15

[0108] In Compound (Id) which corresponds to Compound (I) wherein X—Y—Zis R¹N—C═O (in the formula, R¹ has the same meaning as defined above) orN═C—W² (in the formula, W² has the same meaning as defined above), andR³ is a lower alkyl group, a substituted or unsubstituted aralkyl group,or a lower alkoxyalkyl group, Compound (Ida), which corresponds toCompound (Id) wherein R² is —NR⁷R⁸ (in the formula, R⁷ and R⁸ have thesame meanings as those defined above, respectively), can be obtained byreacting Compound (Idb) which corresponds to Compound (Id) wherein R² isa halogen atom, or said compound in which the halogen atom is replacedwith a suitable leaving group such as a methanesulfonyloxy group, atoluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group, withHNR⁷R⁸ (in the formula, R⁷ and R⁸ have the same meanings as those defiedabove, respectively) in a manner similar to that of Step 10.

[0109] (In the formula, A¹ has the same meaning as the aforementioned A,B² has the same meaning as the aforementioned B, and n, R^(3c), R¹¹,R¹², V¹, V² and X¹—Y¹—Z¹ have the same meanings as those defined above,respectively.)

[0110] Step 16

[0111] Compound (Idc), which corresponds to Compound (Id) wherein R² isa lower alkyl group substituted with —NR¹¹R¹² (in the formula, R¹¹ andR¹² have the same meanings as those defined above, respectively), can beobtained by reacting Compound (Idd), which corresponds to Compound (Id)wherein R² is a lower alkyl group substituted with a suitable leavinggroup such as a halogen atom, a methanesulfonyloxy group, atoluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group, withHNR¹¹R¹² (in the formula, R¹¹ and R¹² have the same meanings as thosedefined above, respectively) in a manner similar to that of Step 10.

[0112] (In the formulas, E represents a lower alkoxy group, and A¹, B²,n, R^(3c), V¹, V² and X¹—Y¹—Z¹ have the same meanings as those definedabove, respectively. The lower alkoxy group has the same meaning asdefined above.)

[0113] Step 17

[0114] Compound (Ide), which corresponds to Compound (Id) wherein R² isa lower alkyl group substituted with a lower alkoxy group, can beobtained by treating Compound (Idd) in a lower alcoholic solution of ametal salt of a corresponding lower alcohol prepared with metallicsodium or a metal hydride such as sodium hydride or potassium hydride.The reaction is performed at a temperature between 0° C. and a boilingpoint of the solvent used and finishes in 1 to 24 hours, preferably in 1to 6 hours.

[0115] (In the formulas, Hal, n, R^(3c), R⁹, R¹⁰, V¹, V² and X¹—Y¹—Z¹have the same meanings as those defined above, respectively.)

[0116] Step 18

[0117] Compound (Idf), which corresponds to Compound (Id) wherein R² is—CONR⁹R¹⁰ (in the formula, R⁹ and R¹⁰ have the same meanings as thosedefined above, respectively), can be obtained by reacting Compound(Idg), which corresponds to Compound (Id) wherein R² is —COHal (in theformula, Hal has the same meaning as defined above), with 2 to 20equivalents, preferably 5 to 10 equivalents, of HNR⁹R¹⁰ (in the formula,R⁹ and R¹⁰ have the same meanings as those defined above, respectively)without a solvent or in a suitable solvent. Examples of the solventinclude, for example, N,N-dimethylformamide, dimethyl sulfoxide and soforth. The reaction is performed at a temperature between 0° C. and roomtemperature, preferably at room temperature, and finishes in 12 to 48hours, preferably in 24 hours.

[0118] (In the formulas, R^(1c) represents a group defined for R¹excluding a hydrogen atom, and n, R^(2a), R^(3c), V¹ and V² have thesame meanings as those defined above, respectively.)

[0119] Step 19

[0120] In Compound (Ie) which corresponds to Compound (I) wherein X—Y—Zis R¹N—C═O (in the formula, R¹ has the same meaning as defined above),R² is a hydrogen atom, a substituted or unsubstituted lower alkyl group,a substituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, and R³ is a lower alkyl group, a substituted orunsubstituted aralkyl group, or a lower alkoxyalkyl group, Compound(Iea), which corresponds to Compound (Ie) wherein R¹ is a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted aryl group, or a substituted orunsubstituted aromatic heterocyclic group, can be obtained by reactingCompound (Ieb), which corresponds to Compound (Ie) wherein R¹ ishydrogen atom, with a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic ring which is substituted with a suitable leaving groupsuch as a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxygroup, or a trifluoromethanesulfonyloxy group in a suitable solvent inthe presence of an inorganic base such as potassium carbonate, sodiumcarbonate or cesium carbonate. The reaction is performed at atemperature between 0° C. and a boiling point of the solvent used,preferably at room temperature, and finishes in 1 to 24 hours,preferably in 1 to 6 hours.

[0121] [In the formulas, W³ represents a substituted or unsubstitutedalicyclic heterocyclic group, —NR⁴R⁵ (in the formula, R⁴ and R⁵ have thesame meanings as those defined above, respectively), —OR⁶ (in theformula, R⁶ has the same meaning as defined above), —SR^(6a) (in theformula, R^(6a) has the same meaning as defined above), a substituted orunsubstituted lower alkyl group, or a cyano group, and n, R^(2a),R^(3a), V¹, V² and W¹ have the same meanings as those defined above,respectively. The alicyclic heterocyclic group, the lower alkyl group,and the substituents of the substituted alicyclic heterocyclic group andthe substituted lower alkyl group have the same meanings as thosedefined above, respectively.]

[0122] Step 20

[0123] In Compound (If) which corresponds to Compound (I) wherein X—Y—Zis N═C—W (in the formula, W has the same meaning as defined above), R²is a hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group, and R³ is a hydrogen atom, a lower alkyl group, or asubstituted or unsubstituted aralkyl group, Compound (Ifa), whichcorresponds to Compound (If) wherein W represents a substituted orunsubstituted alicyclic heterocyclic group, —NR⁴R⁵ (in the formula, R⁴and R⁵ have the same meanings as those defined above, respectively),—OR⁶ (in the formula, R⁶ has the same meaning as defined above),—SR^(6a) (in the formula, R^(6a) has the same meaning as defined above),a substituted or unsubstituted lower alkyl group, or a cyano group, canbe obtained by reacting Compound (Ifb) which corresponds to Compound(If) wherein W is a halogen atom in a suitable solvent with (a) HNR⁴R⁵(in the formula, R⁴ and R⁵ have the same meanings as those definedabove, respectively) or an alicyclic heterocyclic ring in the presenceof an inorganic base such as potassium carbonate, sodium carbonate, orcesium carbonate, or a metal salt of HNR⁴R⁵ (in the formula, R⁴ and R⁵have the same meanings as those defined above, respectively) or analicyclic heterocyclic ring prepared by using a metal hydride such assodium hydride or potassium hydride or a metal lower alkoxide such assodium methoxide, sodium ethoxide, or potassium tert-butoxide, (b) ametal salt of R⁶OH (in the formula, R⁶ has the same meaning as definedabove) or R^(6a)SH (in the formula, R^(6a) has the same meaning asdefined above) prepared with metallic sodium or a metal hydride such assodium hydride or potassium hydride, (c) an alkylating agent such as asubstituted or unsubstituted lower alkyl lithium, or a substituted orunsubstituted lower alkyl magnesium bromide, or (d) a cyanating agentsuch as sodium cyanide or potassium cyanide. Examples of the solventinclude, for example, methanol, ethanol, acetonitrile, tetrahydrofuran,diethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxideand so forth, and these solvents are used each alone or as a mixturethereof. The reaction is performed at a temperature between 0° C. and aboiling point of the solvent used, preferably at a temperature between0° C. and 100° C., and finishes in 1 to 24 hours, preferably in 1 to 5hours.

[0124] Intermediate compounds and target compounds obtained in theaforementioned preparation methods can be isolated and purified bypurification methods ordinarily used in the field of synthetic organicchemistry, for example, neutralization, filtration, extraction, washing,drying, concentration, recrystallization, various chromatographytechniques and or the like. Intermediate compounds may also be used forsubsequent reactions without particular purification. For thepreparation of salts of Compound (I), a compound in a free form can bedissolved or suspended in a suitable solvent, followed by addition of asuitable acid or a base to form a salt, which may be separated andpurified as required. It is also possible to convert a target substanceobtained in a form of a salt into a compound in a free form and thenconvert the resulting product into a desired salt.

[0125] Specific examples of Compound (I) obtainable by theaforementioned preparation methods are shown in Table 1. TABLE 1 (1) (I)

Com- pound No. R¹ R² R³ V^(a) 1 CH₃(CH₂)₂

H

2 CH₃(CH₂)₂

H

3 CH₃(CH₂)₂

H

4 CH₃(CH₂)₂

H

5 CH₃(CH₂)₂

H

6 CH₃(CH₂)₂

H

7 CH₃(CH₂)₂

H

8 CH₃(CH₂)₂ CH₃(CH₂)₂ H

9 CH₃(CH₂)₂

H

10 CH₃(CH₂)₂

H

11 CH₃(CH₂)₂ (CH₃)₃C H

12 CH₃(CH₂)₂

H

13 CH₃(CH₂)₂ H H

[0126] TABLE 1 (2) (I)

Compound No. R¹ R² R³ V^(a) 14

H

15

(CH₃)₃C H

16 CH₂CH₃

H

17 (CH₂)₂CH₃

18 (CH₂)₂CH₃

19 (CH₂)₂CH₃

20 (CH₂)₂CH₃

H

21 (CH₂)₂CH₃

H

22 (CH₂)₂CH₃

H

23 (CH₂)₂CH₃

H

24 (CH₂)₂CH₃

H

25 (CH₂)₂CH₃

H

[0127] TABLE 1 (3) (I)

Compound No. R¹ R² R³ V^(a) 26 (CH₂)₂CH₃

H

27 (CH₂)₂CH₃

H

28 (CH₂)₂CH₃

H

29 (CH₂)₂CH₃

H

30 (CH₂)₂CH₃

H

31 (CH₂)₂CH₃

H

32 (CH₂)₂CH₃

H

33 (CH₂)₂CH₃

H

34 (CH₂)₂CH₃

H

35 CH₃(CH₂)₂ Br

36 CH₃(CH₂)₂ SCH₃

37 CH₃(CH₂)₂

[0128] TABLE 1 (4) (I)

Compound No. R¹ R² R³ V^(a) 38 (CH₂)₂CH₃

H

39 (CH₂)₂CH₃

H

40 (CH₂)₂CH₃

H

41 (CH₂)₂CH₃ CHO

42 (CH₂)₂CH₃ ClCH₂

43 (CH₂)₂CH₃ (CH₃)₂NHCH₂ H

44 (CH₂)₂CH₃

H

45 (CH₂)₂CH₃ CH₃CH₂OCH₂ H

46 (CH₂)₂CH₃

H

47 (CH₂)₂CH₃ CO₂CH₃

48 (CH₂)₂CH₃

49 (CH₂)₂CH₃

H

50 (CH₂)₂CH₃

H

[0129] TABLE 1 (5) (I)

Compound No. R¹ R² R³ V^(a) 51 CH₃(CH₂)₂

H

52 CH₃(CH₂)₂

H

53 CH₃(CH₂)₂

H

54 CH₃(CH₂)₂

H

55 CH₃(CH₂)₂

H

56 CH₃(CH₂)₂

H

57 CH₃(CH₂)₂

H

58 CH₃(CH₂)₂

H

59 CH₃(CH₂)₂

H

[0130] TABLE 1 (6) (I)

Compound No. R¹ R² R³ V^(a) 60 CH₃(CH₂)₂

H

61 CH₃(CH₂)₂

H

62 CH₃(CH₂)₂

H

63 CH₃(CH₂)₂

H

64 CH₃(CH₂)₂ CH₃CH₂SCH₂ H

65 CH₃(CH₂)₂

H

[0131] TABLE 1 (7) (I)

Compound No. W R² R³ V^(a) 66 Cl

67

H

68

H

69

H

70

(CH₃)₃C H

71

H

72

H

73 SCH₃ (CH₃)₃C H

74 CH₂CH₃

H

75 C≡N

H

76

H

[0132] TABLE 1 (8) (I)

Compound No. R¹ R² R³ V^(a) 77

H

78

H

79

H

80

H

81

H

82

H

83

(CH₃)₃C H

84

H

85

H

86

(CH₃)₃C H

[0133] TABLE 1 (9) (I)

Compound No. R¹ R² R³ V¹ V² 87 CH₃(CH₂)₂ CH₃CH₂OCH₂ H

H 88 CH₃(CH₂)₂ CH₃CH₂OCH₂ H H

89 CH₃(CH₂)₂

H H

[0134] Compound (I) or a pharmacologically acceptable salt thereof hasinsulin secretion promoting action in cultured β-cells and hypoglycemicaction in rats, and accordingly, the substance is useful as an activeingredient of a medicament for prophylactic and/or therapeutic treatmentof diabetes. Further, the substance is also useful as an activeingredient of a medicament for prophylactic and/or therapeutic treatmentof various complications of diabetes, for example, retinopathy,nephropathy, neurosis or the like. As the active ingredient of thesemedicaments, one or more substances selected from the group consistingof Compound (I) and pharmacologically acceptable salts thereof, andhydrates thereof and solvates thereof can be used. Although theaforementioned substance, per se, can also be administered, it isgenerally desirable to provide the medicament in a form of apharmaceutical composition comprising the aforementioned substance asthe active ingredient and one or more additives for pharmaceuticalpreparations. These medicaments can be administered to humans andmammals other than human.

[0135] The form of the pharmaceutical composition is not particularlylimited, and an appropriate form most suitable for a purpose oftherapeutic or prophylactic treatment can be selected from forms ofpharmaceutical preparations for oral or parenteral administration.Examples of pharmaceutical preparations suitable for oral administrationinclude, for example, tablets, powders, granules, syrups and the like.Example of pharmaceutical preparations suitable for parenteraladministration include, for example, injections and the like. However,the preparations are not limited to these examples.

[0136] Liquid preparations suitable for oral administration such assyrups can be prepared by using water, saccharides such as sucrose,sorbitol, or fructose, glycols such as polyethylene glycol or propyleneglycol, oils such as sesame oil, olive oil, or soybean oil,preservatives such as p-hydroxybenzoic acid esters, flavors such asstrawberry flavor or peppermint or the like. For the preparation ofsolid preparations such as tablets, powders, and granules, excipientssuch as lactose, glucose, sucrose, or mannitol, disintegrating agentssuch as starch or sodium alginate, lubricants such as magnesium stearateor talc, binders such as polyvinyl alcohol, hydroxypropylcellulose, orgelatin, surface active agents such as fatty acid esters, plasticizerssuch as glycerin or the like may be used.

[0137] Pharmaceutical preparations for injection, which are suitable forparenteral administration, contain the aforementioned substance as theactive ingredient preferably in a sterilized aqueous medium isotonicwith blood of a recipient in a dissolved or suspended state. Forexample, as for injections, a solution can be prepared by using anaqueous medium consisting of saline, a glucose solution, a mixture ofsaline and a glucose solution or the like. To these pharmaceuticalpreparations for parenteral administration, one or more auxiliaryingredients selected from glycols, oils, flavors, preservatives,excipients, disintegrating agents, lubricants, binders, surface activeagents, plasticizers and the like may also be, added.

[0138] Dose and frequency of administration of Compound (I) maypreferably be increased or decreased depending on various factors suchas type and severity of diseases, dosage form, conditions of patientssuch as age and body weight, and presence or absence of complications.In general, Compound (I) may preferably be administered in an amount of1 to 1000 mg/kg per day for an adult dividedly as three or four times ofadministrations.

[0139] Although Compound (I) or a pharmacologically acceptable saltthereof is useful as an active ingredient of a medicament, for example,use of Compound (I) or a pharmacologically acceptable salt thereof isnot limited to this particular purpose.

BEST MODE FOR CARRYING OUT THE INVENTION

[0140] The present invention will be more specifically explained withreference to the following examples. However, the scope of the presentinvention is not limited to the following examples.

REFERENCE EXAMPLE 1 (S)—N-Benzoyl-β-(4-pyridyl)-α-alanine Methyl Ester(Compound A1)

[0141] Methanol (8 mL) was cooled to −5° C., thionyl chloride (685 μL,9.39 mmol, 5.0 equivalents) was dropwise added thereto and the mixturewas stirred for 30 minutes. To the mixture was added(S)—N-(tert-butoxycarbonyl)-β-(4-pyridyl)-α-alanine (500 mg, 1.88 mmol),and the mixture was stirred at the same temperature for 2 hours, thenwarmed to room temperature and stirred for 12 hours. After the solventwas evaporated under reduced pressure, the resulting residue wasdissolved in methylene chloride (15 mL) and to the mixture was addedbenzoyl chloride (240 μL, 1.88 mmol, 1.0 equivalent) and triethylamine(1.05 mL, 7.52 mmol, 4.0 equivalents). The reaction mixture was stirredfor 45 minutes under ice cooling, then warmed to room temperature andstirred for further 4 hours. To the reaction mixture was further addedbenzoyl chloride (120 μL, 0.940 mmol, 0.5 equivalent), the mixture wasstirred for 2 hours, then water (20 mL) was added to the mixture, andthe mixture was extracted with methylene chloride. The resulting organiclayer was washed with saturated aqueous sodium hydrogen carbonate andsaturated aqueous sodium chloride and dried over anhydrous magnesiumsulfate. After the solvent was evaporated, the resulting residue waspurified by silica gel column chromatography (chloroform:methanol=100:0to 98:2) to obtain the title compound (520 mg, 97%).

[0142]¹H-NMR (270 MHz, CDCl₃) δ 3.17 (dd, 1H, J=14.0, 6.8 Hz), 3.30 (dd,1H, J=14.0, 5.8 Hz), 3.72 (s, 3H), 5.09 (m, 1H), 5.15 (brs, 1H), 7.11(d, 2H, J=5.9 Hz), 7.32-7.52 (m, 3H), 7.74 (d, 2H, J=7.3 Hz), 8.42 (d,2H, J=5.9 Hz).

REFERENCE EXAMPLE 2 (S)-2-(N-Benzoylamino)-3-(4-pyridyl)-1-propanol(Compound A2)

[0143] Compound A1 (870 mg, 3.06 mmol) obtained in Reference Example 1was dissolved in ethanol (8 mL) and water (8 mL). To the solution wasadded sodium borohydride (289 mg, 7.65 mmol, 2.5 equivalents), and themixture was stirred for 2 hours under ice cooling. The reaction mixturewas warmed to room temperature, then stirred for 24 hours and adjustedto pH 7 with 4 mol/L hydrochloric acid. The reaction mixture wasconcentrated to an about half volume and then extracted with chloroform,and the resulting organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated to obtain the title compound (550mg, 70%).

[0144]¹H-NMR (270 MHz, CDCl₃) δ 3.02 (dd, 2H, J=7.4, 1.8 Hz), 3.67 (dd,1H, J=11.2, 4.3 Hz), 3.77 (dd, 1H, J=11.2, 3.8 Hz), 4.41 (m, 1H), 6.67(brd, 1H, J=7.9 Hz), 7.22 (d, 2H, J=4.4 Hz), 7.36-7.52 (m, 3H),7.67-7.71 (m, 2H), 8.47 (d, 2H, J=4.4 Hz).

REFERENCE EXAMPLE 3 (S)-2-Amino-3-(4-pyridyl)-1-propanol (Compound A3)

[0145] To Compound A2 (550 mg, 2.15 mmol) obtained in Reference Example2 was added concentrated hydrochloric acid (10 mL), and the mixture wasstirred with heating for 7 hours. After the reaction mixture was cooledand the deposited solid was removed by filtration, the filtrate wasconcentrated under reduced pressure. The resulting oil was dissolved inmethanol (20 mL) and water (1 mL), and to the solution was added BioRadAG-X8 (hydroxide form) until the solution became alkaline. After theresin was removed by filtration, the filtrate was concentrated underreduced pressure to obtain the title compound (310 mg, 95%).

[0146]¹H-NMR (270 MHz, CDCl₃) δ 2.55 (dd, 1H, J=13.5, 8.6 Hz), 2.81 (dd,1H, J=13.5, 5.3 Hz), 3.17 (m, 1H), 3.41 (dd, 1H, J=10.6, 6.9 Hz), 3.63(dd, 1H, J=10.6, 4.0 Hz), 7.15 (d, 2H, J=5.6 Hz), 8.52 (d, 2H, J=5.6Hz).

REFERENCE EXAMPLE 4 2-Amino-3-(2-pyridyl)-1-propanol (Compound A5)

[0147] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(2-pyridyl)-α-alanine as a starting material,which was derived from β-(2-pyridyl)-α-alanine obtained by the methoddescribed in Bulletin Chemical Society Japan (Bull. Chem. Soc. Japan),41, p.1634, 1968.

[0148]¹H-NMR (270 MHz, CDCl₃) δ 2.79 (dd, 1H, J=13.5, 7.6 Hz), 2.97 (dd,1H, J=13.5, 5.6 Hz), 3.26 (m, 1H), 3.45 (m, 1H), 3.57 (dd, 1H, J=11.2,4.3 Hz), 7.17-7.25 (m, 2H), 7.68 (dt, 1H, J=7.6, 2.0 Hz), 8.50 (d, 1H,J=5.0 Hz).

[0149] FAB-MS: m/z 153 (M⁺+1).

REFERENCE EXAMPLE 5 2-Amino-3-(3-pyridyl)-1-propanol (Compound A6)

[0150] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(3-pyridyl)-α-alanine as a starting material,which was derived from β-(3-pyridyl)-α-alanine obtained by the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 29, p.2658,1964.

[0151]¹H-NMR (270 MHz, CDCl₃) δ 2.55 (dd, 1H, J=13.5, 8.3 Hz), 2.81 (dd,1H, J=13.5, 5.3 Hz), 3.09 (m, 1H), 3.40 (m, 1H), 3.57 (dd, 1H, J=10.6,4.3 Hz), 7.26 (dd, 1H, J=7.9, 5.0 Hz), 7.58 (d, 1H, J=7.9 Hz), 8.45-8.47(m, 2H).

[0152] FAB-MS: m/z 153 (M⁺+1).

REFERENCE EXAMPLE 6 2-Amino-3-(2-methylthiazol-4-yl)-1-propanol(Compound A7)

[0153] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(2-methylthiazol-4-yl)-α-alanine as a startingmaterial, which was derived from β-(2-methylthiazol-4-yl)-α-alanineobtained by the method described in Synthesis, p.1145, 1992.

[0154]¹H-NMR (270 MHz, CDCl₃) δ 2.69 (s, 3H), 2.77 (dd, 1H, J=13.9, 7.6Hz), 2.88 (dd, 1H, J=13.9, 5.4 Hz), 3.25 (m, 1H), 3.46 (dd, 1H, J=10.9,5.9 Hz), 3.57 (dd, 1H, J=10.9, 4.6 Hz), 6.82 (s, 1H).

[0155] FAB-MS: m/z 173 (M⁺+1).

REFERENCE EXAMPLE 7 2-Amino-3-(2-pyrazinyl)-1-propanol (Compound A8)

[0156] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(2-pyrazinyl)-α-alanine as a startingmaterial, which was derived from β-(2-pyrazinyl)-α-alanine obtained bythe method described in Journal of Heterocyclic Chemistry (J.Heterocycl. Chem.), 2, p.1, 1965.

[0157]¹H-NMR (270 MHz, CDCl₃) δ 2.84 (dd, 1H, J=13.8, 4.9 Hz), 2.99 (dd,1H, J=13.8, 5.4 Hz), 3.36 (m, 1H), 3.46 (m, 1H), 3.62 (dd, 1H, J=10.8,4.1 Hz), 8.45-8.55 (m, 3H).

[0158] FAB-MS: m/z 154 (M⁺+1).

REFERENCE EXAMPLE 8 2-Amino-3-(4-pyrimidinyl)-1-propanol (Compound A9)

[0159] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(4-pyrimidinyl)-α-alanine as a startingmaterial, which was derived from β-(4-pyrimidinyl)-α-alanine obtained bythe method described in Journal of Heterocyclic Chemistry (J.Heterocycl. Chem.), 2, p.1, 1965.

[0160]¹H-NMR (270 MHz, CDCl₃) δ 2.80 (dd, 1H, J=13.8, 7.8 Hz), 2.95 (dd,1H, J=13.8, 4.6 Hz), 3.38 (m, 1H), 3.48 (m, 1H), 3.61 (dd, 1H, J=10.5,4.3 Hz), 7.23 (d, 1H, J=5.4 Hz), 8.64 (d, 1H, J=5.4 Hz), 9.14 (s, 1H).

[0161] FAB-MS: m/z 154 (M⁺+1).

REFERENCE EXAMPLE 9 2-Amino-3-(4-pyridyl)-1-propanol (Compound A10)

[0162] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by usingN-(tert-butoxycarbonyl)-β-(4-pyridyl)-α-alanine as a starting material,which was derived from β-(4-pyridyl)-α-alanine obtained by the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 23, p.575,1958.

[0163]¹H-NMR (270 MHz, CDCl₃) δ 2.55 (dd, 1H, J=13.2, 8.6 Hz), 2.81 (dd,1H, J=13.2, 5.3 Hz), 3.15 (m, 1H), 3.40 (dd, 1H, J=10.6, 6.9 Hz), 3.47(s, 1H), 3.62 (dd, 1H, J=10.6, 4.0 Hz), 7.16 (d, 2H, J=5.9 Hz), 8.53 (d,2H, J=5.9 Hz).

[0164] FAB-MS: m/z 153 (M⁺+1).

REFERENCE EXAMPLE 10 (R)-2-Amino-3-(4-fluorophenyl)-1-propanol (CompoundA11)

[0165] The title compound was obtained in a manner similar to that inReference Examples 1 to 3 by using(R)—N-(tert-butoxycarbonyl)-4-fluorophenylalanine as a startingmaterial, which was derived from (R)-4-fluorophenylalanine.

[0166]¹H-NMR (270 MHz, CDCl₃) δ 2.51 (dd, 1H, J=13.5, 8.5 Hz), 2.77 (dd,1H, J=13.5, 5.3 Hz), 3.09 (m, 1H), 3.37 (dd, 1H, J=10.5, 6.9 Hz), 3.62(dd, 1H, J=10.5, 4.0 Hz), 6.96-7.06 (m, 2H), 7.12-7.22 (m, 2H).

REFERENCE EXAMPLE 11 (R)-3-Amino-4-phenyl-1-butanol (Compound A12)

[0167] To a solution (70 mL) of lithium aluminum hydride (1.50 g, 39.5mmol, 3.0 equivalents) in tetrahydrofuran was added dropwise a solutionof (R)—N-(benzoyloxy-carbonyl)-3-amino-4-phenylbutanoic acid (4.84 g,13.1 mmol), which was obtained by the method described in Tetrahedron,44, p.5525, 1988 and Journal of Organic Chemistry (J. Org. Chem.), 64,p.6411, 1999, in tetrahydrofuran (30 mL) under ice cooling, and themixture was stirred at room temperature for 30 minutes. After thereaction solution was cooled on ice, excess lithium aluminum hydride wasdecomposed with ethyl acetate and water. The deposited solid was removedby filtration using a filtration aid, and the filtrate was extractedwith chloroform. The organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, and the solventwas evaporated. After the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate: n-hexane=50:50), the resulting(R)—N-(benzyloxycarbonyl)-3-amino-4-phenyl-1-butanol (1.37 g, 5.09 mmol)was dissolved in methanol (30 mL), and to the solution were added 20%palladium hydroxide/carbon (200 mg) and ammonium formate (1.30 g, 20.6mmol, 4.1 equivalents), and then the mixture was stirred for 1 hour withheating. After the catalyst was removed by using a filtration aid, thesolvent was evaporated. To the residue was added ethyl acetate, and thedeposited solid was collected by filtration to obtain the title compound(730 mg, 87%).

[0168]¹H-NMR (270 MHz, DMSO-d₆) δ 1.61 (q, 2H, J=6.3 Hz), 2.77 (dd, 1H,J=13.5, 8.4 Hz), 3.00 (dd, 1H, J=13.5, 5.7 Hz), 3.41 (m, 1H), 3.49 (dt,2H, J=10.8, 4.6 Hz), 7.22-7.36 (m, 5H).

REFERENCE EXAMPLE 12 3-Amino-2-benzyl-1-propanol (Compound A13)

[0169] The title compound (1.29 g, 59%) was obtained by the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 43, p.2539,1978 using 2-benzyl-3-oxopropionic acid ethyl ester (2.73 g, 13.3 mmol)as a starting material, which was obtained by the method described inTetrahedron, 38, p.3597, 1982.

[0170]¹H-NMR (270 MHz, CDCl₃) δ 1.99 (m, 1H), 2.48 (dd, 1H, J=13.6, 7.3Hz), 2.59 (dd, 1H, J=13.6, 7.3 Hz), 2.75 (dd, 1H, J=12.2, 8.6 Hz), 3.07(ddd, 1H, J=12.2, 3.6, 1.3 Hz), 3.66 (dd, 1H, J=10.6, 7.6 Hz), 3.81(ddd, 1H, J=10.6, 3.3, 1.3 Hz), 7.15-7.31 (m, 5H).

REFERENCE EXAMPLE 13 3-Amino-2-(3-pyridyl)-1-propanol (Compound A14)

[0171] The title compound (1.17 g, 39%) was obtained by the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 43, p.2539,1978 using 3-pyridylacetic acid ethyl ester (2.50 g, 15.1 mmol) as astarting material, which was obtained by the method described in Journalof Organic Chemistry (J. Org. Chem.), 43, 2539, 1978.

[0172]¹H-NMR (270 MHz, DMSO-d₆) δ 2.71 (dt,2H, J=13.5, 7.0 Hz),2.89(quin, 1H, J=5.1 Hz), 3.58 (dd, 1H, J=10.5, 6.2 Hz), 3.67 (dd, 1H,J=10.5, 6.2 Hz), 7.29 (dd, 1H, J=7.8, 5.4 Hz), 7.61 (dt, 1H, J=5.4, 2.2Hz), 8.37-8.41 (m, 2H).

REFERENCE EXAMPLE 14 6-Methylthio-3,8-dipropyl-7H-purin-2(3H)-one(Compound B2)

[0173] 3,8-Dipropylxanthine (12.3 g, 52.2 mmol), which was obtained bythe method described in Journal of Medicinal Chemistry (J. Med. Chem.),16 (35), p.3066, 1992, was dissolved in pyridine (185 mL). To thesolution was added phosphorus pentasulfide (16.4 g, 73.7 mmol, 1.4equivalents), and the mixture was stirred with heating at 130° C. for 5hours. After the reaction solution was poured into ice water and themixture was extracted with chloroform, the organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform:methanol=95:5) to obtain athione compound (8.80 g, 67%). The thione compound (8.80 g, 34.7 mmol)was dissolved in a mixture of 0.5 mol/L aqueous sodium hydroxide (120mL) and ethanol (40 mL) and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture was added methyl iodide (4.00mL, 64.2 mmol, 1.9 equivalents), and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was neutralized with 2mol/L aqueous hydrochloric acid, and the deposited crystals werecollected by filtration to obtain the title compound (7.40 g, 80%).

[0174]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.02 (t, 3H,J=7.3 Hz), 1.85 (m, 4H), 2.50 (s, 3H), 2.89 (t, 2H, J=7.3 Hz), 4.22 (t,2H, J=7.6 Hz), 13.9 (brs, 1H).

REFERENCE EXAMPLE 158-Cyclohexyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B3)

[0175] Phosphorus pentasulfide (27.1 g, 122 mmol, 1.5 equivalents) wassuspended in pyridine (150 mL) and the mixture was heated to 100° C. Tothe suspension was gradually added 5,6-diamino-1-propyluracil (15.0 g,81.3 mmol), which was obtained by the method described in Journal ofMedicinal Chemistry (J. Med. Chem.), 32 (6), p.1231, 1989, with heatingand stirring, and then the mixture was stirred for 7 hours. After thereaction solution was cooled on ice, the deposited solid was separatedby filtration using a filtration aid and washed with pyridine. Thefiltrate was concentrated, to the residue was added water (90 mL), andthe mixture was stirred under reflux with heating for about 40 minutesuntil intense foaming ceased. The reaction mixture was cooled on ice andthen further stirred overnight at room temperature. The depositedyellowish green ocher solid was collected by filtration, sufficientlywashed with water and dried under reduced pressure to obtain5,6-diamino-1,2-dihydro-4-mercapto-2-oxo-1-propylpyrimidine (CompoundB4, 11.3 g, 69%). Compound B4 (10.0 g, 50.0 mmol) was suspended in1,4-dioxane (200 mL) and water (100 mL), to the suspension were addedcyclohexanecarboxylic acid (8.06 mL, 65.0 mmol, 1.3 equivalents) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g,85.0 mmol, 1.7 equivalents) at room temperature, and then the mixturewas stirred overnight. To the reaction mixture was added 2 mol/L aqueoussodium hydroxide (100 mL), and the mixture was stirred with heating for2.5 hours. The reaction mixture was cooled on an ice bath, adjusted topH 6 with 4 mol/L hydrochloric acid and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was dissolved in 0.5 mol/L aqueoussodium hydroxide (150 mL), and to the solution was added methyl iodide(4.70 mL, 75.0 mmol, 1.5 equivalents) and the mixture was stirredovernight at room temperature. The reaction mixture was cooled on an icebath, adjusted to pH 6.5 with 4 mol/L aqueous hydrochloric acid andextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated. Then, the residue waspurified by silica gel column chromatography (chloroform:methanol=100:0to 96:4) to obtain the title compound (11.8 g, 78%).

[0176]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.85-2.11 (m,8H), 2.32 (s, 3H), 2.33-2.62 (m, 4H), 3.77 (m, 1H), 4.16 (t, 2H, J=7.6Hz).

REFERENCE EXAMPLE 168-Cyclobutyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B5)

[0177] 8-Cyclobutyl-3-(n-propyl)-6-thioxanthine (1.00 g, 3.79 mmol),which was obtained by the method described in EP 256692A, was dissolvedin 0.5 mol/L aqueous sodium hydroxide (15 mL), and the solution wasstirred at room temperature for 30 minutes. To the reaction mixture wasadded methyl iodide (350 μL, 5.71 mmol, 1.5 equivalents), and themixture was stirred at room temperature for 18 hours. The reactionsolution was neutralized with 4 mol/L aqueous hydrochloric acid, and thedeposited crystals were collected by filtration to obtain the titlecompound (910 mg, 86%).

[0178]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.85-2.11 (m,4H), 2.08 (s, 3H), 2.33-2.62 (m, 4H), 3.76 (m, 1H), 4.25 (t, 2H, J=7.4Hz).

REFERENCE EXAMPLE 178-(tert-Butyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (CompoundB6)

[0179] Compound B4 (7.00 g, 35.2 mmol) was dissolved in pyridine (70mL). To the solution was added pivaloyl chloride (4.74 mL, 38.5 mmol,1.1 equivalents), and the mixture was stirred at room temperature for 18hours. The reaction mixture was concentrated, to the residue was added 2mol/L aqueous sodium hydroxide (100 mL), and the mixture was stirredwith heating for 2 hours. The reaction mixture was adjusted to pH 6.5with 4 mol/L aqueous hydrochloric acid under ice cooling and extractedwith chloroform. After the organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated, water was added to theresidue. The deposited solid was collected by filtration and dried underreduced pressure to obtain a thione compound (9.21 g, 99%). Then, thetitle compound (9.65 g, 100%) was obtained in a manner similar to thatin Reference Example 16.

[0180]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.5 Hz), 1.46 (s, 9H),1.83-1.91 (m, 2H), 2.12 (s, 3H), 4.24 (t, 2H, J=7.3 Hz), 12.3 (brs, 1H).

REFERENCE EXAMPLE 188-(1-Methylcyclohexyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B7)

[0181] The title compound (1.73 g, 54%) was obtained from Compound B4(2.00 g, 10.0 mmol) and 1-methylcyclohexanecarbonyl chloride (2.27 g,14.1 mmol, 1.4 equivalents) in a manner similar to that in ReferenceExample 17.

[0182]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.4 Hz), 1.35 (s, 3H),1.44-1.61 (m, 8H), 1.82-1.90 (m, 2H), 2.18-2.26 (m, 2H), 2.26 (s, 3H),4.23 (t, 2H, J=7.1 Hz), 11.4 (brs, 1H).

REFERENCE EXAMPLE 198-Cyclopentyl-3-cyclopropylmethyl-6-methylthio-7H-purin-2(3H)-one(Compound B9)

[0183] 5,6-Diamino-1-cyclopropylmethyluracil (3.00 g, 15.3 mmol), whichwas obtained by the method described in EP386683A, was suspended in amixed solvent of 1,4-dioxane (50 mL) and water (25 mL). To thesuspension were added cyclopentanecarboxylic acid (2.16 mL, 19.9 mmol,1.3 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (5.00 g, 26.0 mmol, 1.7 equivalents), and the mixture wasstirred overnight at room temperature. To the reaction mixture was added2 mol/L aqueous sodium hydroxide (20 mL), and the mixture was refluxedwith heating for 5 hours. The reaction solution was cooled on ice, andadjusted to pH 6.5 with addition of 4 mol/L aqueous hydrochloric acid.The deposited solid was collected by filtration, washed with water anddiisopropyl alcohol and dried under reduced pressure to obtain axanthine compound. Phosphorus pentasulfide (2.53 g, 11.4 mmol) wasdissolved in pyridine (33 mL), to the solution was added the xanthinecompound, and then the mixture was stirred at 100° C. for 4 hours. Afterthe solvent was evaporated under reduced pressure, ice was added to theresulting residue to triturate the solid, and the solid was collected byfiltration and dried under reduced pressure to obtain a thione compound.The thione compound was dissolved in 0.5 mol/L aqueous sodium hydroxide(50 mL), to the solution was added methyl iodide (1.04 mL, 16.7 mmol)under ice cooling, and the mixture was stirred at room temperature for18 hours. The reaction mixture was adjusted to pH 6.5 with 4 mol/Laqueous hydrochloric acid and then extracted with chloroform. After theresulting organic layer was dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (chloroform:methanol=100:0to 98:2) to obtain the title compound (1.66 g, 37%).

[0184]¹H-NMR (270 MHz, CDCl₃) δ 0.44-0.57 (m, 4H), 1.26-2.17 (m, 9H),2.00 (s, 3H), 3.31 (quin, 1H, J=8.2 Hz), 4.17 (d, 2H, J=7.3 Hz), 13.6(brs, 1H).

REFERENCE EXAMPLE 208-(tert-Butyl)-3-cyclopropylmethyl-6-methylthio-7H-purin-2(3H)-one(Compound B10)

[0185] 5,6-Diamino-1-cyclopropylmethyluracil (3.00 g, 15.3 mmol), whichwas obtained by the method described in EP386683A, was dissolved inpyridine (60 mL), to the solution was added pivaloyl chloride (2.07 mL,16.8 mmol, 1.1 equivalents), and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was concentrated underreduced pressure, to the concentrate was added 2 mol/L aqueous sodiumhydroxide (20 mL), and the mixture was stirred with heating for 4 hours.The reaction mixture was adjusted to pH 6.5 with 4 mol/L aqueoushydrochloric acid under ice cooling, and the deposited solid werecollected by filtration, washed with water and dried under reducedpressure to obtain a xanthine compound. Then, the title compound (3.28g, 73%) was obtained in a manner similar to that in Reference Example16.

[0186]¹H-NMR (270 MHz, DMSO-d₆) δ 0.42-0.44 (m, 4H), 1.31 (m, 1H), 1.37(s, 9H), 2.51 (s, 3H), 3.90 (d, 2H, J=6.9 Hz), 12.8 (brs, 1H).

REFERENCE EXAMPLE 218-Cyclopentyl-3-ethyl-6-methylthio-7H-purin-2(3H)-one (Compound B11)

[0187] In a manner similar to that in Reference Example 15, the titlecompound (3.49 g, 81%) was obtained from

[0188] 5,6-diamino-1-ethyl-1,2-dihydro-4-mercapto-2-oxopyrimidine (5.85g, 31.5 mmol), which was synthesized from 5,6-diamino-1-ethyluracilobtained by the method described in U.S. Pat. No. 4,338,319.

[0189]¹H-NMR (270 MHz, DMSO-d₆) δ 1.21 (t, 3H, J=6.9 Hz), 1.55-2.09 (m,8H), 2.56 (s, 3H), 3.19 (quin, 1H, J=8.2 Hz), 4.04 (q, 2H, J=7.0 Hz).

REFERENCE EXAMPLE 228-Ethoxymethyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (CompoundB12)

[0190] The title compound was obtained from Compound B4 and ethoxyacetic acid in a manner similar to that in Reference Example 15.

[0191]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.29 (t, 3H,J=6.9 Hz), 1.85 (q, 2H, J=7.3 Hz), 2.61 (s, 3H), 3.69 (q, 2H, J=6.9 Hz),4.17 (t, 2H, J=7.3 Hz), 4.71 (s, 2H), 10.6 (br, 1H).

REFERENCE EXAMPLE 236-Methylthio-3-(n-propyl)-2-(tetrahydrofuran-2-yl)-7H-purin-2(3H)-one(Compound B13)

[0192] The title compound was obtained from Compound B4 and2-tetrahydrofurancarboxylic acid in a manner similar to that inReference Example 15.

[0193]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.78-1.91 (m,2H), 1.94-2.08 (m, 2H), 2.24 (m, 1H), 2.45 (m, 1H), 2.53 (s, 3H), 3.96(m, 1H), 4.07-4.20 (m, 3H), 5.16 (dd, 1H, J=7.7, 5.8 Hz), 11.1 (brs,1H).

REFERENCE EXAMPLE 248-(1-Ethoxymethyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B14)

[0194] To an ethanol solution of sodium ethoxide, which was prepared byadding metallic sodium to anhydrous ethanol, was added 2-bromopropionicacid, and the mixture was stirred with heating for 90 minutes. After theethanol was evaporated, a saturated ammonium chloride solution was addedto the residue and the mixture was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated. The resulting residue was condensed with Compound B4 ina manner similar to that in Reference Example 15 to obtain the titlecompound.

[0195]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.29 (t, 3H,J=7.0 Hz), 1.58 (d, 3H, J=6.6 Hz), 1.85 (q, 2H, J=7.3 Hz), 2.66 (s, 3H),3.57 (m, 1H), 3.66 (m, 1H), 4.17 (t, 2H, J=7.3 Hz), 4.72 (q, 1H, J=6.6Hz), 9.96 (brs, 1H).

REFERENCE EXAMPLE 256-Methylthio-3-(n-propyl)-2-(tetrahydropyran-4-yl)-7H-purin-2(3H)-one(Compound B15)

[0196] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 and 4-tetrahydropyrancarboxylicacid, which was obtained by the method described in Hervetica ChemicaActa (Helv. Chem. Acta), 80, p.1528, 1997.

[0197]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.81-1.90 (m,2H), 1.98-2.15 (m, 4H), 2.04 (s, 3H), 3.20 (m, 1H), 3.52 (dt, 2H,J=11.8, 3.0 Hz), 4.02-4.14 (m, 2H), 4.26 (t, 2H, J=7.3 Hz).

REFERENCE EXAMPLE 266-Methylthio-8-(4-oxocyclohexyl)-3-(n-propyl)-7H-purin-2(3H)-one(Compound B16)

[0198] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 and 4-oxocyclohexanecarboxylicacid, which was derived from 4-oxocyclohexanecarboxylic acid ethylester.

[0199]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t,3H, J=7.3 Hz), 1.83-2.60 (m,10H),2.12 (s, 3H), 3.48 (m, 1H), 4.25 (t, 2H, J=7.3 Hz).

REFERENCE EXAMPLE 278-(1,3-Dioxolane-2-spirocyclopentan-2′-yl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B17)

[0200] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 and1,3-dioxolane-2-spirocyclopentane, which was derived from2-oxocyclopentanecarboxylic acid.

[0201]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.73-2.04 (m,8H), 2.39 (s, 3H), 3.51 (t, 1H, J=8.6 Hz), 3.75-3.94 (m, 4H), 4.22 (t,2H, J=7.3 Hz).

REFERENCE EXAMPLE 288-Benzyloxymethyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (CompoundB18)

[0202] The title compound was obtained from Compound B4 andbenzyloxyacetic acid in a manner similar to that in Reference Example15.

[0203]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.83 (q, 2H,J=7.4 Hz), 2.57 (s, 3H), 4.15 (t, 2H, J=7.3 Hz), 4.69 (s, 2H), 4.76 (s,2H), 7.32-7.38 (m, 5H), 10.9 (brs, 1H).

REFERENCE EXAMPLE 298-(α-Methoxybenzyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B19)

[0204] The title compound was obtained from Compound B4 and α-methoxyphenylacetic acid in a manner similar to that in ReferenceExample 15.

[0205]¹H-NMR (270 MHz, CDCl₃) δ 0.93 (t, 3H, J=7.3 Hz), 1.83 (q, 2H,J=7.3 Hz), 2.20 (s, 3H), 3.44 (s, 3H), 4.19 (t, 2H, J=7.3 Hz), 5.52 (s,1H), 7.21-7.30 (m, 3H), 7.42-7.47 (m, 2H).

REFERENCE EXAMPLE 308-(2-Methoxyethyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B20)

[0206] The title compound was obtained from Compound B4 and3-methoxypropionic acid in a manner similar to that in Reference Example15.

[0207]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.4 Hz), 1.78-1.92 (m,2H), 2.56 (s, 3H), 3.14 (t, 2H, J=5.9 Hz), 3.44 (s, 3H), 3.79 (t, 2H,J=5.9 Hz), 4.15-4.20 (m, 2H), 10.9 (brs, 1H).

REFERENCE EXAMPLE 318-(2-Carboxyethyl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B21)

[0208] The title compound was obtained from Compound B4 and succinicacid monoethyl ester in a manner similar to that in Reference Example15.

[0209]¹H-NMR (270 MHz, DMSO-d₆) δ 0.87 (t, 3H, J=7.6 Hz), 1.63-1.71 (m,2H), 2.56 (s, 3H), 2.74 (t, 2H, J=6.9 Hz), 2.97 (t, 2H, J=6.9 Hz), 3.96(t, 2H, J=7.3 Hz).

REFERENCE EXAMPLE 328-(1-Methylsulfonylpiperidin-4-yl)-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B22)

[0210] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 andN-methylsulfonylisonipecotinic acid, which was derived fromisonipecotinic acid.

[0211]¹H-NMR (270 MHz, DMSO-d₆) δ 0.88 (t, 3H, J=7.2 Hz), 1.65-1.91 (m,4H), 1.97-2.09 (m, 2H), 2.57 (s, 3H), 2.89 (s, 3H), 2.90-3.01 (m, 3H),3.57-3.66 (m, 2H), 3.84-4.01 (m, 2H), 13.1 (brs, 1H).

REFERENCE EXAMPLE 332-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B23)

[0212] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 andN-(tert-butoxycarbonyl)isonipecotinic acid, which was derived fromisonipecotinic acid.

[0213]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.46 (s, 9H),1.83-2.04 (m, 6H), 2.09 (s, 3H), 2.83-2.92 (m, 2H), 3.14 (m, 1H),4.14-4.27 (m, 4H).

REFERENCE EXAMPLE 348-[trans-4-(Benzyloxycarbonylaminomethyl)cyclohexyl]-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B24)

[0214] In a manner similar to that in Reference Example 15, the titlecompound was obtained from Compound B4 andtrans-4-(benzyloxycarbonylaminomethyl)-cyclohexanecarboxylic acid, whichwas derived from trans-4-(aminomethyl)-cyclohexanecarboxylic acid.

[0215]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.4 Hz), 1.04-1.12 (m,4H), 1.43-1.99 (m, 7H), 2.11 (s, 3H), 2.85 (m, 1H), 3.05-3.15 (m, 2H),4.16-4.24 (m, 2H), 4.86 (m, 1H), 5.09 (s, 2H), 7.30-7.36 (m, 5H).

REFERENCE EXAMPLE 358-Ethylthiomethyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one (CompoundB25)

[0216] The title compound was obtained from Compound B4 and ethylthioacetate in a manner similar to that in Reference Example 15.

[0217]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.6 Hz), 1.26 (t, 3H,J=7.4 Hz), 1.88 (q, 2H, J=7.4 Hz), 2.51 (s, 3H), 2.62 (q, 2H, J=7.6 Hz),3.93 (s, 2H), 4.20 (q, 2H, J=7.0 Hz), 11.6 (br, 1H).

REFERENCE EXAMPLE 36 7-Benzyl-2,6-dichloro-8-cyclopentylpurine (CompoundC1)

[0218] To 7-benzyl-8-cyclopentyl-3-(4-methoxybenzyl)xanthine (6.81 g,15.8 mmol), which was obtained by the method described in InternationalPatent Publication in Japanese (Kohyo) No. 8-500344, was addedphosphorus oxychloride (60.0 mL, 644 mmol, 41 equivalents), and themixture was refluxed with heating for 6 hours. The reaction solution wasconcentrated under reduced pressure and the solvent was furtherazeotroped with toluene. To the residue was carefully added ethylacetate and saturated aqueous sodium hydrogen carbonate, and the mixturewas stirred at room temperature for 30 minutes. The organic layer wasextracted with ethyl acetate, the extract was washed with saturatedaqueous sodium chloride and dried over anhydrous sodium sulfate, andthen the solvent was evaporated. The residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=33:67) to obtain the titlecompound (4.94 g, 90%).

[0219]¹H-NMR (270 MHz, CDCl₃) δ 1.56-1.70 (m, 2H), 1.88-2.09 (m, 6H),3.23 (quin, 1H, J=7.9 Hz), 5.70 (s, 2H), 6.94-6.97 (m, 2H), 7.32-7.37(m, 3H).

REFERENCE EXAMPLE 37(R)-7-Benzyl-2-chloro-8-cyclopentyl-6-(1-hydroxy-3-phenylpropan-2-ylamino)purine(Compound C2)

[0220] Compound C1 (1.64 g, 4.72 mmol) was dissolved inN,N-dimethylformamide (15 mL), and to the solution were added(R)-phenylalaminol (1.07 g, 7.08 mmol, 1.5 equivalents) anddiisopropylethylamine (1.64 mL, 9.41 mmol, 2.0 equivalents), and thenthe mixture was stirred at room temperature for 24 hours. After thereaction solution was concentrated under reduced pressure, ethyl acetateand water were added to the residue and the deposited solid (1.14 g) wascollected by filtration. The filtrate was extracted with ethyl acetate,the organic layer was washed with saturated aqueous sodium chloride anddried over anhydrous sodium sulfate, and then the solvent wasevaporated. The residue was purified by silica gel column chromatography(chloroform:methanol=90:10) to obtain the title compound (1.88 g, 86% intotal).

[0221]¹H-NMR (270 MHz, CDCl₃) δ 1.48-1.73 (m, 2H), 1.76-2.07 (m, 6H),2.67-2.75 (m, 2H), 3.08 (dd, 1H, J=13.3, 8.5 Hz), 3.11 (quin, 1H, J=8.4Hz), 3.31 (dd, 1H, J=13.3, 4.8 Hz), 4.37 (m, 1H), 5.55 (d, 1H, J=15.9Hz), 5.65 (d, 1H, J=15.9 Hz), 7.10-7.38 (m, 10H).

REFERENCE EXAMPLE 38(R)-7-Benzyl-2-chloro-8-cyclopentyl-6-[3-(4-fluorophenyl)-1-hydroxypropan-2-ylamino]purine(Compound C3)

[0222] The title compound (1.75 g, 77%) was obtained from Compound Cl(1.64 g, 4.72 mmol) and Compound All (1.20 g, 7.09 mmol, 1.5equivalents) in a manner similar to that in Reference Example 37.

[0223]¹H-NMR (270 MHz, CDCl₃) δ 1.53-1.62 (m, 2H), 1.80-2.02 (m, 6H),2.61-2.73 (m, 2H), 3.04 (dd, 1H, J=13.6, 7.6 Hz), 3.11-3.31 (m, 2H),4.38 (m, 1H), 5.52 (d, 1H, J=15.8 Hz), 5.62 (d, 1H, J=15.8 Hz),6.84-7.41 (m, 9H).

REFERENCE EXAMPLE 39 6-Amino-5-benzylamino-1-(4-methoxybenzyl)uracil(Compound C4)

[0224] 5,6-Diamino-1-(4-methoxybenzyl)uracil (15.1 g, 57.5 mmol), whichwas obtained by the method described in International Patent Publicationin Japanese No. 8-500344, was dissolved in acetic acid (25 mL) and water(100 mL). To the solution was added benzaldehyde (7.00 mL, 68.9 mmol,1.2 equivalents), and the mixture was stirred at room temperature for 90minutes. To the reaction solution was added water (100 mL), and thedeposited imine compound (17.4 g, 86%) was collected by filtration. Theimine compound was dissolved in methanol (250 mL) and dichloromethane(250 mL), to the solution were added sodium cyanoborohydride (4.28 g,63.7 mmol, 1.2 equivalents) and then acetic acid (3.0 mL), and themixture was stirred at room temperature for 12 hours. After the reactionsolution was concentrated, methanol was added to the residue, and thedeposited solid was collected by filtration, washed with methanol anddried to obtain the title compound (10.2 g, 58%).

[0225]¹H-NMR (270 MHz, DMSO-d₆) δ 3.73 (s, 3H), 3.84 (s, 2H), 4.94 (s,2H), 6.36 (brs, 2H), 6.87 (d, 2H, J=8.6 Hz), 7.05 (d, 2H, J=8.6 Hz),7.24-7.34 (m, 5H).

REFERENCE EXAMPLE 40 7-Benzyl-8-(tert-butyl)-3-(4-methoxybenzyl)xanthine(Compound C5)

[0226] Compound C4 (10.2 g, 29.0 mmol) was dissolved in pyridine (10mL), to the solution was added pivaloyl chloride (3.50 mL, 30.5 mmol,1.1 equivalents), and then the mixture was stirred at room temperaturefor 24 hours. After the reaction solution was concentrated, ethylacetate was added to the resulting residue, and the deposited solid(7.51 g, 59%) was collected by filtration. The resulting solid wasdissolved in 2 mol/L aqueous sodium hydroxide (50 mL), the mixture wasrefluxed with heating for 1 hour, and the reaction mixture was adjustedto pH 6 with 4 mol/L hydrochloric acid under ice cooling. The depositedsolid was collected by filtration and dried under reduced pressure toobtain the title compound (6.61 g, 92%).

[0227]¹H-NMR (270 MHz, DMSO-d₆) δ 1.28 (s, 9H), 3.72 (s, 3H), 5.02 (s,2H), 5.75 (brs, 2H), 6.88 (d, 2H, J=8.6 Hz), 6.95 (d, 2H, J=7.3 Hz),7.22-7.33 (m, 3H), 7.38 (d, 2H, J=8.6 Hz).

REFERENCE EXAMPLE 41(R)-7-Benzyl-8-(tert-butyl)-2-chloro-6-(1-hydroxy-3-phenylpropan-2-ylamino)purine(Compound C6)

[0228] 7-Benzyl-8-(tert-butyl)-2,6-dichloropurine (2.18 g, 41%) wasobtained from Compound C5 (6.61 g, 15.8 mmol) in a manner similar tothat in Reference Example 36, and the title compound was obtained in amanner similar to that in Reference Example 37.

[0229]¹H-NMR (270 MHz, CDCl₃) δ 1.51 (s, 9H), 2.52-2.61 (m, 2H), 3.28(dd, 1H, J=13.5, 8.6 Hz), 3.42 (dd, 1H, J=13.5, 4.9 Hz), 4.36 (m, 1H),4.75 (brd, 1H, J=8.5 Hz), 5.46 (d, 1H, J=15.7 Hz), 5.68 (d, 1H, J=15.7Hz), 6.93-6.97 (m, 2H), 7.08 (d, 2H, J=7.6 Hz), 7.22-7.41 (m, 6H).

REFERENCE EXAMPLE 42 8-(tert-Butyl)-6-chloro-2-methylthiopurine(Compound C7)

[0230] 4,5-Diamino-6-hydroxy-2-mercaptopyrimidine (15.0 g, 94.8 mmol)was dissolved in pyridine (200 mL), to the solution was added pivaloylchloride (14.0 mL, 0.11 mol, 1.2 equivalents), and then the mixture wasstirred at room temperature for 12 hours. After the reaction solutionwas concentrated, to the residue was added acetone, and the depositedsolid (18.5 g, 81%) was collected by filtration. The resulting solid wasdissolved in 0.5 mol/L aqueous sodium hydroxide (150 mL), to thesolution was added methyl iodide (5.30 mL, 85.1 mmol, 1.1 equivalents),and the mixture was stirred overnight at room temperature. After thereaction mixture was cooled on an ice bath and adjusted to pH 6.5 with 4mol/L hydrochloric acid, the deposited solid (19.6 g, 99%) was collectedby filtration. To the resulting solid was added phosphorus oxychloride(60 mL, 0.643 mol, 8.4 equivalents) and the mixture was refluxed withheating for 5 hours. After the reaction solution was concentrated underreduced pressure and the solvent was azeotroped with toluene, ethylacetate and saturated aqueous sodium hydrogen carbonate were carefullyadded to the residue, and then the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was extracted withethyl acetate, the organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, and then thesolvent was evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=95:5) to obtain the title compound(16.7 g, 90%).

[0231]¹H-NMR (270 MHz, CDCl₃) δ 1.55 (s, 9H), 2.59 (s, 3H), 9.86 (br,1H).

REFERENCE EXAMPLE 43(R)-8-(tert-Butyl)-6-(1-hydroxy-3-phenylpropan-2-ylamino)-2-methylsulfonyl-7H-purine(Compound C8)

[0232] Compound C7 (16.7 g, 62.1 mmol) was dissolved in n-butanol (50mL), to the solution were added (R)-phenylalaminol (14.0 g, 92.6 mmol,1.5 equivalents) and diisopropylethylamine (16.4 mL, 94.1 mmol, 1.5equivalents), and the mixture was stirred at 150° C. for 1 hour. Thereaction solution was concentrated under reduced pressure, to theconcentrate were added saturated aqueous ammonium chloride and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform:methanol=95:5) to obtain(R)-8-(tert-butyl)-6-(1-hydroxy-3-phenylpropan-2-ylamino)-2-methylthio-7H-purine(Compound C9, 9.50 g, 39%). Compound C9 (5.63 g, 15.8 mmol) wasdissolved in methanol (200 mL) and water (50 mL), to the solution wasadded a monopersulfate compound (19.4 g, 31.5 mmol, 2.0 equivalents),and then the mixture was stirred at room temperature for 2 hours. Afterthe reaction solution was concentrated, the resulting residue wasextracted with chloroform, the organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=95:5) to obtain the title compound(7.89 g, 96%).

[0233]¹H-NMR (270 MHz, DMSO-d₆) δ 2.06 (s, 9H), 2.86-3.00 (m, 2H), 3.38(s, 3H),3.51-3.62 (m, 2H), 4.42 (br, 1H), 4.82 (m, 1H), 7.10-7.34 (m,5H), 7.90 (br, 1H), 12.9 (br, 1H).

REFERENCE EXAMPLE 44(R)-8-Cyclopentyl-6-(1-hydroxy-3-phenylpropan-2-ylamino)-2-methylsulfonyl-7H-purine(Compound C10)

[0234] The title compound was obtained from4,5-diamino-6-hydroxy-2-mercaptopyrimidine and cyclopentylcarbonylchloride in a manner similar to that in Reference Examples 42 and 43.

[0235]¹H-NMR (270 MHz, DMSO-d₆) δ 1.68-2.08 (m, 8H), 2.86-2.97 (m, 2H),3.25 (m, 1H), 3.33 (s, 3H),3.50-3.62 (m, 2H), 4.48 (br, 1H), 4.87 (m,1H), 7.13-7.28 (m, 5H), 7.84 (br, 1H), 13.1 (br, 1H).

EXAMPLE 1(S)-2-Cyclopentyl-7,8-dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 1)

[0236] 8-Cyclopentyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one(Compound B1, 576 mg, 1.97 mmol), which was obtained by the methoddescribed in Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.),30, p.241, 1993, and Compound A3 (300 mg, 1.97 mmol, 1.0 equivalent)obtained in Reference Examples 1-3 were stirred in pyridine (1 mL) at150° C. for 5 hours. The solvent was evaporated under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 90:10) to obtain(S)-8-cyclopentyl-6-[1-hydroxy-3-(4-pyridyl)propan-2-ylamino]-3-(n-propyl)-7H-purin-2(3H)-one(Compound 1a, 578 mg, 74%).

[0237] To Compound 1a (578 mg, 1.46 mmol) was added thionyl chloride(5.0 mL, 68.5 mmol, 47 equivalents) and the mixture was stirred at 60°C. for 2 hours. Excess thionyl chloride was evaporated, to the resultingresidue were added chloroform (10 mL) and saturated aqueous sodiumhydrogen carbonate (10 mL), and the mixture was stirred at roomtemperature for 12 hours. The reaction mixture was extracted withchloroform, the organic layer was washed with saturated aqueous sodiumchloride and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=98:2), and chloroform andmethanol were added to the residue. The deposited crystals werecollected by filtration to obtain the title compound (310 mg, 56%) as awhite solid.

[0238] Compound 1a was also obtained by the method described below.

[0239] OXONE® (Aldrich, 2.46 g, 4.00 mmol, 4.0 equivalents), water (10mL) and chloroform (10 mL) were mixed and cooled to 0-5° C. To thereaction mixture were added Compound B1 (292 mg, 1.00 mmol) and thentetrabutylammonium hydrogensulfate (136 mg, 0.40 mmol, 0.4 equivalents),and the mixture was stirred at the same temperature for 2 hours. Phaseseparation was carried out by using chloroform, and the resultingorganic layer was dried over anhydrous magnesium sulfate and filtered.To the filtrate were added Compounds A3 (152 mg, 1.00 mmol, 1.0equivalent) obtained in Reference Examples 1-3 andN,N-diisopropylethylamine (178 μL, 1.00 mmol, 1.0 equivalent), and themixture was concentrated. To the resulting residue was added pyridine (4mL), and the mixture was stirred at 50° C. for 4 hours. To the reactionmixture was further added Compound A3 (76 mg, 0.50 mmol, 0.5equivalent), and the mixture was stirred for 3 hours. After the reactionmixture was concentrated, the residue was purified by silica gel columnchromatography (ethyl acetate:methanol) to obtain Compound 1a (300 mg,76%).

[0240] Melting point: 256-257° C. (chloroform/methanol)

[0241]¹H-NMR (270 MHz, DMSO-d₆) δ 0.83 (t, 3H, J=7.4 Hz), 1.57-1.95 (m,10H), 2.88 (d, 2H, J=7.3 Hz), 3.06 (m, 1H), 3.55 (m, 1H), 3.79 (t, 2H,J=7.3 Hz), 3.91 (t, 1H, J=10.4 Hz), 4.53 (m, 1H), 7.32 (d, 2H, J=5.6Hz), 8.45 (d, 2H, J=5.6 Hz).

[0242] IR (KBr): 1693, 1656, 1009, 744 cm⁻¹

[0243] TOF-MS: m/z 379 (M⁺+1).

[0244] Elemental Analysis for C₂₁H₂₆N₆O

[0245] Calculated (%): C, 66.64; H, 6.92; N, 22.21.

[0246] Found (%): C, 66.71; H, 7.00; N, 22.14.

EXAMPLE 2(R)-2-Cyclopentyl-7,8-dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-oneD-tartrate (Compound 2)

[0247] In a manner similar to that in Example 1, the title compound inthe free form (Compound 2a, 20.4 g, 51%) was obtained from Compound B1(30.7 g, 105 mmol) and (R)-2-amino-3-(4-pyridyl)-1-propanol (CompoundA4, 16.0 g, 105 mmol, 1.0 equivalent), which was obtained from(R)—N-(tert-butoxycarbonyl)-β-(4-pyridyl)-α-alanine in a manner similarto that in Reference Examples 1-3. To Compound 2a (18.0 g, 47.6 mmol)was added D-tartaric acid (7.14 g, 47.6 mmol, 1.0 equivalent) andrecrystallization was performed from ethanol and water to obtain thetitle compound (23.5 g, 92%) as a white solid.

[0248] Melting point: 223-224° C. (ethanol/water)

[0249]¹H-NMR (270 MHz, DMSO-d₆) δ 0.85 (t, 3H, J=7.4 Hz), 1.59-2.02 (m,10H), 2.93 (d, 2H, J=6.9 Hz), 3.23 (m, 1H), 3.60 (dd, 1H, J=10.9, 6.9Hz), 3.82 (t, 2H, J=7.1 Hz), 3.98 (t, 1H, J=10.4 Hz), 4.27 (s, 2H), 4.58(m, 1H), 7.37 (d, 2H, J=5.6 Hz), 8.47 (d, 2H, J=5.6 Hz).

[0250] IR (KBr): 1716, 1679, 1577 cm⁻¹

[0251] TOF-MS: m/z 379 (M⁺+1).

[0252] Elemental Analysis for C₂₁H₂₆N₆₀.C₄H₆O₆.0.5H₂O

[0253] Calculated (%): C, 55.86; H, 6.19; N, 15.63.

[0254] Found (%): C, 56.03; H, 6.06; N, 15.45.

EXAMPLE 32-Cyclopentyl-7,8-dihydro-8-(2-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 3)

[0255] In a manner similar to that in Example 1, the title compound (103mg, 20%) was obtained as a white solid from Compound B1 (483 mg, 1.64mmol) and Compound A5 (505 mg, 3.28 mmol, 2.0 equivalents) prepared inReference Example 4.

[0256] Melting point: 147-150° C. (methanol/chloroform)

[0257]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.63-1.89 (m,8H), 1.98-2.08 (m, 2H), 3.01-3.19 (m, 3H), 3.87 (dd, 1H, J=11.2, 6.8Hz), 4.04 (t, 2H, J=7.2 Hz), 4.16 (t, 1H, J=10.0 Hz), 4.70 (m, 1H),7.09-7.16 (m, 2H), 7.53 (dt, 1H, J=8.0, 1.7 Hz), 8.53 (d, 1H, J=4.6 Hz).

[0258] IR (CHCl₃): 1693, 1655 cm⁻¹

[0259] EI-MS: m/z 378 (M⁺).

EXAMPLE 42-Cyclopentyl-7,8-dihydro-8-(3-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 4)

[0260] In a manner similar to that in Example 1, the title compound (51mg, 14%) was obtained from Compound B1 (290 mg, 0.99 mmol) and CompoundA6 (300 mg, 1.97 mmol, 2.0 equivalents) prepared in Reference Example 5.

[0261] Melting point: 247-250° C. (ethyl acetate/diethyl ether)

[0262]¹H-NMR (270 MHz, DMSO-d₆) δ 0.90 (t, 3H, J=7.6 Hz), 1.67-1.76 (m,8H), 2.08 (m, 2H), 3.29-3.31 (m, 3H), 3.98-4.08 (m, 3H), 4.31 (t, 1H,J=10.5 Hz), 4.85 (m, 1H), 8.02 (t, 1H, J=6.0 Hz), 8.53 (d, 1H, J=7.8Hz), 8.85 (d, 1H, J=5.2 Hz), 8.90 (s, 1H).

[0263] IR (CHCl₃): 1718, 1678 cm⁻¹

[0264] FAB-MS: m/z 379 (M⁺+1).

EXAMPLE 52-Cyclopentyl-7,8-dihydro-8-(2-methylthiazol-4-ylmethyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 5)

[0265] In a manner similar to that in Example 1, the title compound inthe free form was obtained from Compound B1 (450 mg, 1.53 mmol) andCompound A7 (526 mg, 3.06 mmol, 2.0 equivalents) prepared in ReferenceExample 6, and then it was converted into hydrochloride with 4 mol/Lhydrogen chloride in dioxane to obtain the title compound (100 mg, 15%)as a white solid.

[0266] Melting point: 125-128° C. (ethanol)

[0267]¹H-NMR (270 MHz, DMSO-d₆) δ 0.89 (t, 3H, J=7.2 Hz), 1.65-1.77 (m,8H), 2.01-2.11 (m, 2H), 2.64 (s, 3H), 3.15 (d, 2H, J=6.6 Hz), 3.31 (m,1H), 3.98 (t, 2H, J=7.3 Hz), 4.07 (dd, 1H, J=11.3, 6.3 Hz), 4.29 (t, 1H,J=11.3 Hz), 4.76 (m, 1H), 7.34 (s, 1H), 10.6 (brs, 1H).

[0268] IR (CHCl₃): 1716, 1676, 1584 cm⁻¹

[0269] FAB-MS: m/z 399 (M⁺+1).

EXAMPLE 62-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(2-pyrazinylmethyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 6)

[0270] In a manner similar to that in Example 1, the title compound (130mg, 10%) was obtained as a white solid from Compound B1 (954 mg, 3.27mmol) and Compound A8 (500 mg, 3.27 mmol, 1.0 equivalent) prepared inReference Example 7.

[0271] Melting point: 225-228° C. (methanol/chloroform)

[0272]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.6 Hz), 1.71-1.93 (m,8H), 2.12-2.21 (m, 2H), 3.22-3.32 (m, 2H), 3.49 (dd, 1H, J=15.7, 5.9Hz), 4.11 (t, 2H, J=7.6 Hz), 4.22 (dd, 1H, J=11.9, 6.8 Hz), 4.51 (dd,1H, J=11.9, 10.3 Hz), 4.98 (m, 1H), 8.52 (d, 1H, J=2.2 Hz), 8.56 (s,1H), 8.58 (d, 1H, J=2.2 Hz).

[0273] IR (CHCl₃): 1716, 1684, 1587 cm⁻¹

[0274] FAB-MS: m/z 380 (M⁺+1).

EXAMPLE 72-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(4-pyrimidinylmethyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 7)

[0275] In a manner similar to that in Example 1, the title compound (32mg, 3%) was obtained as a white solid from Compound B1 (954 mg, 3.27mmol) and Compound A9 (500 mg, 3.27 mmol, 1.0 equivalent) prepared inReference Example 8.

[0276] Melting point: 255-260° C. (methanol/ethyl acetate)

[0277]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.67-1.82 (m,8H), 1.99-2.09 (m, 2H), 3.02-3.22 (m, 3H), 3.88 (dd, 1H, J=11.6, 4.1Hz), 4.01 (t, 2H, J=7.6 Hz), 4.21 (t, 1H, J=11.6 Hz), 4.80 (m, 1H), 7.23(d, 1H, J=5.1 Hz), 8.62 (d, 1H, J=5.1 Hz), 9.13 (s, 1H).

[0278] IR (CHCl₃): 1690, 1655, 1591 cm⁻¹

[0279] FAB-MS: m/z 380 (M⁺+1).

EXAMPLE 87,8-Dihydro-8-(4-picolyl)-2,4-dipropyl-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 8)

[0280] In a manner similar to that in Example 1, the title compound (195mg, 55%) was obtained as a white solid from Compound B2 (266 mg, 1.00mmol) prepared in Reference Example 14 and Compound A10 (304 mg, 2.00mmol, 2.0 equivalents) prepared in Reference Example 9.

[0281] Melting point: 270-274° C. (ethyl acetate/diethyl ether)

[0282]¹H-NMR (270 MHz, CDCl₃) δ 0.95-1.02 (m, 6H), 1.71-1.87 (m, 4H),2.69-2.75 (m, 2H), 2.83-2.93 (m, 2H), 3.72 (dd, 1H, J=11.2, 6.6 Hz),4.01 (t, 2H, J=5.9 Hz), 4.10 (t, 1H, J=11.2 Hz), 4.35 (m, 1H), 7.25 (d,2H, J=4.6 Hz), 8.55 (d, 2H, J=4.6 Hz).

[0283] IR (CHCl₃): 1690, 1653 cm⁻¹

[0284] EI-MS: m/z 352 (M⁺).

[0285] Elemental Analysis for C₁₉H₂₄N₆O

[0286] Calculated (%): C, 64.75; H, 6.86; N, 23.85.

[0287] Found (%): C, 64.80; H, 7.00; N, 24.02.

EXAMPLE 9(R)-2-Cyclohexyl-7,8-dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 9)

[0288] In a manner similar to that in Example 1, the title compound (510mg, 40%) was obtained as a white solid from Compound B3 (1.00 g, 3.27mmol) prepared in Reference Example 15 and Compound A4 (750 mg, 4.93mmol, 1.5 equivalents).

[0289] Melting point: 262-263° C. (ethanol)

[0290]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.5 Hz), 1.20-1.58 (m,6H), 1.70-1.86 (m, 4H), 2.01-2.05 (m, 2H), 2.76 (m, 1H), 2.88 (dd, 1H,J=13.3, 5.8 Hz), 2.95 (dd, 1H, J=13.2, 7.6 Hz), 3.69 (dd, 1H, J=11.2,6.9 Hz), 3.98 (t, 2H, J=7.5 Hz), 4.07 (t, 1H, J=10.6 Hz), 4.49 (m, 1H),7.24 (d, 2H, J=4.6 Hz), 8.55 (d, 2H, J=4.6 Hz).

[0291] IR (KBr): 2929, 1687, 1660, 746 cm⁻¹

[0292] TOF-MS: m/z 393 (M⁺+1).

[0293] Elemental Analysis for C₂₂H₂₈N₆O

[0294] Calculated (%): C, 67.32; H, 7.19; N, 21.41.

[0295] Found (%): C, 67.85; H, 7.54; N, 21.57.

EXAMPLE 10(R)-2-Cyclobutyl-7,8-dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-oneD-tartrate (Compound 10)

[0296] In a manner similar to that in Example 1, the title compound inthe free form (Compound 10a, 100 mg, 11%) was obtained from Compound B5(700 mg, 2.52 mmol) prepared in Reference Example 16 and Compound A4(570 mg, 3.75 mmol, 1.5 equivalents). To a solution (1 mL) of Compound10a (100 mg, 0.27 mmol) in methanol was added a solution (1 mL) ofD-tartaric acid (83 mg, 0.27 mmol, 1.0 equivalent) in methanol, and themixture was concentrated. Then the resulting solid was recrystallizedfrom ethanol and water to obtain the title compound (60 mg, 43%) as awhite solid.

[0297] Melting point: 203-204° C. (ethanol/water)

[0298]¹H-NMR (270 MHz, CDCl₃) δ 0.86 (t, 3H, J=7.6 Hz), 1.60-1.68 (m,2H), 1.85-2.02 (m, 2H), 2.25-2.35 (m, 4H), 2.94 (d, 2H, J=7.0 Hz), 3.54(m,1H), 3.62 (dd, 1H, J=10.3, 7.0 Hz), 3.84 (t, 2H, J=7.6 Hz), 3.99 (t,1H, J=10.5 Hz), 4.59 (m, 1H), 7.33 (d, 2H, J=5.9 Hz), 8.47 (d, 2H, J=5.9Hz).

[0299] IR (KBr): 1714, 1681, 1585 cm⁻¹

[0300] TOF-MS: m/z 365 (M⁺+1).

[0301] Elemental Analysis for C₂₀H₂₄N₆₀.C₄H₆O₆.0.25H₂O

[0302] Calculated (%): C, 55.53; H, 5.92; N, 16.19.

[0303] Found (%): C, 55.48; H, 5.89; N, 16.12.

EXAMPLE 112-(tert-Butyl)-7,8-dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 11)

[0304] In a manner similar to that in Example 1, the title compound (231mg, 63%) was obtained as a white solid from Compound B6 (280 mg, 1.00mmol) prepared in Reference Example 17 and Compound A10 (304 mg, 2.00mmol, 2.0 equivalents) prepared in Reference Example 9.

[0305] Melting point: 293-295° C. (ethyl acetate/diethyl ether)

[0306]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.40 (s, 9H),1.74-1.84 (m, 2H), 2.86-2.96 (m, 2H), 3.66 (dd, 1H, J=10.9, 7.3 Hz),3.99 (t, 2H, J=7.2 Hz), 4.10 (t, 1H, J=10.9 Hz), 4.55 (m, 1H), 7.29 (d,2H, J=4.6 Hz), 8.65 (d, 2H, J=4.6 Hz).

[0307] IR (CHCl₃): 1690, 1655 cm⁻¹

[0308] EI-MS: m/z 366 (M⁺).

[0309] Elemental Analysis for C₂₀H₂₆N₆₀

[0310] Calculated (%): C, 65.55; H, 7.15; N, 22.93.

[0311] Found (%): C, 65.40; H, 7.25; N, 22.98.

EXAMPLE 127,8-Dihydro-2-(1-methylcyclohexyl)-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 12)

[0312] In a manner similar to that in Example 1, the title compound inthe free form was obtained from Compound B7 (300 mg, 0.94 mmol) preparedin Reference Example 18 and Compound A10 (200 mg, 1.32 mmol, 1.4equivalents) prepared in Reference Example 9. The resulting product wasconverted into hydrochloride with a 4 mol/L solution of hydrogenchloride in dioxane and it was recrystallized from hexane and ethylacetate to obtain the title compound (240 mg, 53%) as a white solid.

[0313] Melting point: 149-150° C. (hexane/ethyl acetate)

[0314]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.4 Hz), 1.30 (s, 3H),1.24-1.76 (m, 10H), 2.08-2.17 (m, 2H), 3.45 (m, 1H), 3.59 (m, 1H),4.05-4.11 (m, 3H), 4.68 (m, 1H), 5.20 (m, 1H), 8.19 (d, 2H, J=4.6 Hz),8.89 (d, 2H, J=4.6 Hz).

[0315] IR (KBr): 2809, 1716, 1679, 1589, 742 cm⁻¹

[0316] FAB-MS: m/z 407 (M⁺+1).

[0317] Elemental Analysis for C₂₃H₃₀N₆O.2HCl.2H₂O

[0318] Calculated (%): C, 53.59; H, 7.04; N, 16.30.

[0319] Found (%): C, 53.48; H, 7.06; N, 16.09.

EXAMPLE 137,8-Dihydro-8-(4-picolyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 13)

[0320] 6-Methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B8, 6.80g, 30.3 mmol), which was obtained by the method described in Journal ofHeterocyclic Chemistry (J. Heterocycl. Chem.), 30, p.241, 1993, wasdissolved in N,N-dimethylformamide (100 mL). To the solution were addedpotassium carbonate (8.40 g, 60.8 mmol, 2.0 equivalents) and benzylbromide (3.90 mL, 33.1 mmol, 1.1 equivalents), and the mixture wasstirred at room temperature for 2 hours. After the reaction mixture wasconcentrated, to the residue was added water, and the resulting crystalswere washed with water and diethyl ether and dried under reducedpressure to obtain a 7-benzyl compound (Compound 13a, 7.22 g, 75%).Compound 13a (2.00 g, 6.36 mmol) was dissolved in pyridine (30 mL), tothe solution was added Compound A10 (1.90 g, 12.8 mmol, 2.0 equivalents)obtained in Reference Example 9, and the mixture was stirred underreflux with heating for 10 hours. After the pyridine was evaporated, theresidue was directly purified by silica gel column chromatography(chloroform:methanol=10:1) to obtain an adduct (940 mg, 35%). To theresulting adduct (940 mg, 2.25 mmol) was added thionyl chloride (5 mL)and the mixture was stirred with heating at 60° C. for 2.5 hours. Afterthe thionyl chloride was evaporated, the residue was neutralized withsaturated aqueous sodium hydrogen carbonate and the mixture wasextracted with chloroform. The organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=98:2) to obtain a cyclized compound(570 mg, 64%). The resulting cyclized compound (20 mg, 0.05 mmol) wasdissolved in methanol (2 mL), to the solution were added 20% palladiumhydroxide/carbon (10 mg) and ammonium formate (20 mg, 0.35 mmol, 7.0equivalents), and then the mixture was refluxed for 4 hours. After thecatalyst was removed by filtration, the reaction mixture wasconcentrated and neutralized with saturated aqueous sodium hydrogencarbonate. The reaction solution was extracted with chloroform, theorganic layer was washed with saturated aqueous sodium chloride anddried, and then the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform:methanol=95:5) to obtainthe title compound (10 mg, 23%).

[0321]¹H-NMR (270 MHz, CDCl₃) δ 0.99 (t, 3H, J=7.3 Hz), 1.82 (q, 2H,J=7.3 Hz), 2.94 (m, 2H), 3.84 (dd, 1H, J=11.2, 5.9 Hz), 4.06 (t, 2H,J=7.3 Hz), 4.11 (t, 1H, J=10.9 Hz), 4.30 (m, 1H), 7.15 (d, 2H, J=5.6Hz), 7.65 (s, 1H), 8.50 (d, 2H, J=5.9 Hz).

[0322] EI-MS: m/z 308 (M⁺).

EXAMPLE 142-Cyclopentyl-4-cyclopropylmethyl-7,8-dihydro-8-(4-picolyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 14)

[0323] In a manner similar to that in Example 1, the title compound inthe free form (500 mg, 78%) was obtained from Compound B9 (500 mg, 1.71mmol) prepared in Reference Example 19 and Compound A10 (350 mg, 2.32mmol, 1.4 equivalents) prepared in Reference Example 9. The resultingproduct was converted into hydrochloride with a 4 mol/L solution ofhydrogen chloride in dioxane and it was recrystallized from ethanol toobtain the title compound (540 mg, 71%) as a white solid.

[0324] Melting point: 240-241° C. (ethanol)

[0325]¹H-NMR (270 MHz, DMSO-d₆) δ 0.47-0.50 (m, 4H), 1.25 (m, 1H),1.76-1.90 (m, 6H), 2.06-2.20 (m, 2H), 3.28-3.38 (m, 3H), 3.92 (d, 2H,J=6.9 Hz), 4.06 (m, 1H), 4.34 (t, 1H, J=9.2 Hz), 4.87 (m, 1H), 7.95 (d,2H, J=6.3 Hz), 8.86 (d, 2H, J=6.3 Hz).

[0326] IR (KBr): 1720, 1673, 1637, 746 cm⁻¹

[0327] FAB-MS: m/z 391 (M⁺+1).

[0328] Elemental Analysis for C₂₂H₂₆N₆.2HCl.1.2H₂O

[0329] Calculated (%): C, 54.48; H, 6.32; N, 17.33.

[0330] Found (%): C, 54.51; H, 6.41; N, 17.14.

EXAMPLE 152-(tert-Butyl)-4-cyclopropylmethyl-7,8-dihydro-8-(4-picolyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 15)

[0331] In a manner similar to that in Example 1, the title compound inthe free form was obtained from Compound B10 (700 mg, 2.45 mmol)prepared in Reference Example 20 and Compound A10 (500 mg, 3.33 mmol,1.4 equivalents) prepared in Reference Example 9. The resulting productwas converted into hydrochloride with a 4 mol/L solution of hydrogenchloride in dioxane and it was recrystallized from ethanol to obtain thetitle compound (380 mg, 35%) as a white solid.

[0332] Melting point: 205-206° C. (ethanol)

[0333]¹H-NMR (270 MHz, DMSO-d₆) δ 0.46-0.55 (m, 4H), 1.37 (m, 1H), 1.44(s, 9H), 3.34-3.59 (m, 2H), 4.02 (d, 2H, J=7.3 Hz), 4.19 (dd, 1H,J=11.9, 6.3 Hz), 4.51 (t, 1H, J=11.1 Hz), 4.96 (m, 1H), 7.55 (brs, 1H),8.15 (d, 2H, J=6.3 Hz), 8.76-8.85 (m, 2H), 11.0 (brs, 1H), 13.2 (brs,1H).

[0334] IR (KBr): 2983, 1716, 1673, 1589, 746 cm⁻¹

[0335] TOF-MS: m/z 379 (M⁺+1).

[0336] Elemental Analysis for C₂₁H₂₆N₆₀.2HCl.2.5H₂O

[0337] Calculated (%): C, 50.81; H, 6.70; N, 16.93.

[0338] Found (%): C, 51.15; H, 6.68; N, 16.76.

EXAMPLE 162-Cyclopentyl-4-ethyl-7,8-dihydro-8-(4-picolyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 16)

[0339] In a manner similar to that in Example 1, the title compound inthe free form (100 mg, 19%) was obtained from Compound Bl (410 mg, 1.51mmol) prepared in Reference Example 21 and Compound A10 (310 mg, 2.00mmol, 1.5 equivalents) prepared in Reference Example 9. The resultingproduct was converted into hydrochloride with a 4 mol/L solution ofhydrogen chloride in dioxane and it was recrystallized from hexane andethanol to obtain the title compound (60 mg, 9%).

[0340] Melting point: 180-181° C. (hexane/ethanol)

[0341]¹H-NMR (270 MHz, DMSO-d₆) δ 1.25 (t, 3H, J=6.9 Hz), 1.60-1.90 (m,6H), 2.00-2.20 (m, 2H), 3.25-3.45 (m, 3H), 3.95-4.15 (m, 3H), 4.32 (t,1H, J=10.7 Hz), 4.87 (m, 1H), 7.96 (d, 2H, J=5.8 Hz), 8.87 (d, 2H, J=5.8Hz).

[0342] IR (KBr): 1716, 1679, 1583, 1512, 742 cm⁻¹

[0343] TOF-MS: m/z 364 (M⁺).

[0344] Elemental Analysis for C₂₀H₂₄N₆₀.2HCl.2H₂O

[0345] Calculated(%): C, 50.74; H, 6.39; N, 17.75.

[0346] Found (%): C, 51.15; H, 6.33; N, 17.51.

EXAMPLE 171-Benzyl-2-cyclopentyl-7,8-dihydro-8-methylsulfonyloxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 17)

[0347] Compound B1 (1.17 g, 4.00 mmol) was dissolved inN,N-dimethylformamide (20 mL), to the solution were added potassiumcarbonate (607 mg, 4.40 mmol, 1.1 equivalents) and benzyl bromide (523μL, 4.40 mmol, 1.1 equivalents), and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was further added benzylbromide (48 μL, 0.40 mmol, 0.1 equivalent), the mixture was stirred at60° C. for 1 hour, and then methanol was added to the mixture. Thereaction mixture was partitioned with ethyl acetate and water, and theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated. Then, the residue was purified by silica gelcolumn chromatography (chloroform). To the resulting ocher syrup-likesubstance was added dl-serinol (547 mg, 6.00 mmol), and the mixture wasstirred at 150° C. for 4 hours. The reaction mixture was purified bysilica gel column chromatography (chloroform:methanol=98:2 to 90:10) andthe resulting substance was recrystallized from chloroform and diethylether to obtain white crystals (500 mg). The resulting crystals weredissolved in dichloromethane (5 mL), to the solution were addedmethanesulfonyl chloride (275 p L, 3.54 mmol) and diisopropylethylamine(923 μL, 5.31 mmol), and the mixture was stirred at room temperature for2 hours. The reaction mixture was partitioned with chloroform and water,and the resulting organic layer was dried over anhydrous magnesiumsulfate. After the organic layer was concentrated, the residue wasrecrystallized from diethyl ether and hexane to obtain the titlecompound (500 mg, 26%) as a light brown solid.

[0348]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.6 Hz), 1.73-1.81 (m,10H), 2.84 (s, 3H), 2.92 (m, 1H), 3.81 (dd, 1H, J=11.2, 7.0 Hz), 3.96(t, 2H, J=7.3 Hz), 3.99 (m, 1H), 4.22 (dd, 1H, J=10.0, 5.1 Hz), 4.30(dd, 1H, J=10.0, 4.3 Hz), 4.53 (m, 1H), 5.44 (d, 1H, J=16.5 Hz), 5.53(d, 1H, J=16.5 Hz), 7.12 (d, 2H, J=6.8 Hz), 7.26-7.35 (m, 3H).

EXAMPLE 182-Cyclopentyl-7,8-dihydro-8-methylsulfonyloxymethyl-1-methoxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 18)

[0349] Compound B1 (10.2 g, 34.8 mmol) was dissolved inN,N-dimethylformamide (100 mL), to the solution were added potassiumcarbonate (10.6 g, 76.6 mmol, 2.2 equivalents) and chloromethyl methylether (5.30 mL, 70.1 mmol, 2.0 equivalents), and the mixture was stirredat 60° C. for 4 hours. The reaction mixture was partitioned with ethylacetate and water, and the organic layer was washed with water and driedover anhydrous magnesium sulfate. The organic layer was concentrated,then to the concentrate was added dl-serinol (5.00 g, 36.2 mmol), andthe mixture was stirred at 150° C. for 4 hours. The reaction mixture waspurified by silica gel column chromatography (ethylacetate:methanol=95:5 to 75:25) to obtain orange oil (10.0 g). Theresulting oil was dissolved in dichloromethane (100 mL), to the solutionwere added methanesulfonyl chloride (8.12 mL, 104 mmol) anddiisopropylethylamine (19.0 mL, 139 mmol), and the mixture was stirredat room temperature for 2 hours. The reaction mixture was partitionedwith chloroform and water, and the organic layer was dried overanhydrous magnesium sulfate. The reaction mixture was concentrated andthe residue was purified by silica gel column chromatography (ethylacetate:methanol=100:0 to 90:10) to obtain the title compound (7.48 g,49%) as an orange solid.

[0350]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.69-2.05 (m,10H), 3.05 (s, 3H), 3.20 (m, 1H), 3.38 (s, 3H), 3.85 (dd, 1H, J=11.6,6.5 Hz), 3.94-4.06 (m, 3H), 4.27 (dd, 1H, J=10.5, 5.7 Hz), 4.37 (dd, 1H,J=10.5, 4.3 Hz), 4.59 (m, 1H), 5.59 (s, 2H).

EXAMPLE 192-Cyclopentyl-8-(1,3-dioxoisoindolin-2-ylmethyl)-7,8-dihydro-1-methoxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 19)

[0351] Compound 18 (500 mg, 0.98 mmol) obtained in Example 18 wasdissolved in N,N-dimethylformamide (10 mL), to the solution was addedphthalimide potassium salt (485 mg, 2.62 mmol, 2.7 equivalents), and themixture was stirred at 120° C. for 4 hours. The reaction mixture waspartitioned with ethyl acetate and water, and the organic layer waswashed with saturated aqueous sodium hydrogen carbonate and dried overanhydrous magnesium sulfate. After the reaction mixture wasconcentrated, the residue was crystallized from dichloromethane anddiethyl ether to obtain the title compound (500 mg, 78%) as whitecrystals.

[0352]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.6 Hz), 1.59-1.99 (m,10H), 3.18 (m, 1H), 3.34 (s, 3H), 3.70-3.98 (m, 6H), 4.69 (m, 1H), 5.54(s, 2H), 7.73 (dd, 2H, J=5.7, 3.2 Hz), 7.87 (dd, 2H, J=5.7, 3.2 Hz).

EXAMPLE 208-Aminomethyl-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 20)

[0353] Compound 19 (574 mg, 1.31 mmol) obtained in Example 19 wasdissolved in methanol (5 mL), to the solution was added hydrazinemonohydrate (1 mL), and the mixture was stirred overnight at roomtemperature. The reaction mixture was partitioned with chloroform andwater, and the organic layer was washed with 4 mol/L aqueous sodiumhydroxide and dried over anhydrous magnesium sulfate. The organic layerwas concentrated, to the concentrate were added a 4 mol/L solution ofhydrogen chloride in dioxane (4 mL) and methanol (4 mL), and the mixturewas stirred under reflux with heating for 2 hours. The reaction mixturewas concentrated, and then the residue was crystallized from methanoland diethyl ether to obtain the title compound (320 mg, 84%) as whitecrystals.

[0354]¹H-NMR (270 MHz, DMSO-d₆) δ 0.91 (t, 3H, J=7.0 Hz), 1.69-1.78 (m,8H), 2.06-2.09 (m, 2H), 2.50 (m, 1H), 3.11-3.21 (m, 2H), 3.91-4.09 (m,2H), 4.20 (dd, 1H, J=12.2, 6.2 Hz), 4.30 (t, 1H, J=11.2 Hz), 4.73 (m,1H), 8.44 (brs, 3H).

EXAMPLE 212-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(1-pyrazolylmethyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 21)

[0355] Compound 17 (100 mg, 0.21 mmol) obtained in Example 17 wasdissolved in N,N-dimethylformamide (1 mL), to the solution were addedpyrazole (28 mg, 0.42 mmol, 2.0 equivalents), and cesium carbonate (137mg, 0.42 mmol, 2.0 equivalents) and the mixture was stirred at 120° C.for 2 hours. The reaction mixture was partitioned with ethyl acetate andwater, and the organic layer was washed with water and dried overanhydrous magnesium sulfate. After the organic layer was concentrated,diethyl ether and hexane were added to the concentrate and the resultingwhite solid (66 mg) was collected by filtration. The resulting productwas dissolved in methanol (1 mL), to the solution were added ammoniumformate (132 mg, 2.10 mmol) and 20% palladium hydroxide/carbon (30 mg),and then the mixture was stirred under reflux with heating for 3 hours.The reaction mixture was filtered by using Celite and concentrated, thento the concentrate were added ammonium formate (150 mg) and 20%palladium hydroxide/carbon (50 mg), and the mixture was stirred underreflux with heating for 4 hours. The reaction mixture was filtered byusing Celite and concentrated, and the residue was purified by silicagel column chromatography (chloroform:methanol=10:1) to obtain the titlecompound (40 mg, 52%) as a white solid.

[0356] Melting point: 138-140° C. (ethyl acetate)

[0357]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.6 Hz), 1.68-1.81 (m,8H), 1.98-2.08 (m, 2H), 3.07 (m, 1H), 3.85 (dd, 1H, J=11.9, 6.2 Hz),3.97-4.07 (m, 3H), 4.20-4.30 (m, 2H), 4.62 (m, 1H), 6.09 (s, 1H), 7.37(s, 1H), 7.46 (s, 1H).

[0358] IR (CHCl₃): 1686, 1655 cm⁻¹

[0359] FAB-MS: m/z 368 (M⁺+1).

EXAMPLE 222-Cyclopentyl-7,8-dihydro-8-(1-imidazolylmethyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 22)

[0360] In a manner similar to that in Example 21, the title compound (10mg, 13%) was obtained as a white solid from Compound 17 (100 mg, 0.21mmol) obtained in Example 17 and imidazole (38 mg, 0.42 mmol, 2.0equivalents).

[0361] Melting point: 158-160° C. (methanol/ethyl acetate)

[0362]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.6 Hz), 1.68-1.78 (m,8H), 2.01-2.11 (m, 2H), 3.15 (m, 1H), 3.69 (dd, 1H, J=11.3, 7.0 Hz),3.94 (t, 2H, J=7.6 Hz), 4.03-4.11 (m, 2H), 4.24 (dd, 1H, J=14.0, 4.1Hz), 4.52 (m, 1H), 6.98 (s, 1H), 7.02 (s, 1H), 7.76 (s, 1H).

[0363] IR (CHCl₃): 1686, 1655 cm⁻¹

[0364] FAB-MS: m/z 368 (M⁺+1).

EXAMPLE 232-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(1,2,4-triazol-1-ylmethyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 23)

[0365] In a manner similar to that in Example 21, the title compound (70mg, 46%) was obtained as a white solid from Compound 17 (200 mg, 0.42mmol) obtained in Example 17 and 1,2,4-triazole (57 mg, 0.83 mmol, 2.0equivalents).

[0366] Melting point: 225-230° C. (ethyl acetate/diethyl ether)

[0367]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.6 Hz), 1.71-1.82 (m,8H), 2.04-2.14 (m, 2H), 3.15 (m, 1H), 3.88-3.98 (m, 3H), 4.09 (t, 1H,J=10.0 Hz), 4.38 (t, 2H, J=4.3 Hz), 4.69 (m, 1H), 7.91 (s, 1H), 8.24 (s,1H).

[0368] IR (CHCl₃): 1687, 1654, 1649 cm⁻¹

[0369] FAB-MS: m/z 369 (M⁺+1).

EXAMPLE 242-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(1-pyrrolylmethyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 24)

[0370] Compound 20 (100 mg, 0.26 mmol) obtained in Example 20 and2,5-dimethoxytetrahydrofuran (67 μL, 0.51 mmol, 2.0 equivalents) weredissolved in N,N-dimethylformamide (2 mL) and the mixture was stirred at80° C. for 2 hours. The reaction mixture was partitioned with ethylacetate and water, and the organic layer was washed with water and driedover anhydrous magnesium sulfate. After the organic layer wasconcentrated, the residue was purified by silica gel columnchromatography (ethyl acetate) to obtain the title compound (56 mg, 60%)as a light yellow solid.

[0371] Melting point: 135-140° C. (ethyl acetate)

[0372]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t,3H, J=7.6 Hz), 1.65-1.94 (m,8H),1.99-2.09 (m, 2H), 3.08 (quin, 1H, J=8.1 Hz), 3.66 (m, 1H), 3.86-4.08(m, 6H), 6.04 (t, 2H, J=2.2 Hz), 6.61 (t, 2H, J=2.2 Hz)

[0373] IR (CHCl₃): 1689, 1653 cm⁻¹

[0374] FAB-MS: m/z 367 (M⁺+1).

EXAMPLE 258-(1-Benzimidazolylmethyl)-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 25)

[0375] Compound 18 (100 mg, 0.23 mmol) obtained in Example 18 wasdissolved in N,N-dimethylformamide (1 mL), to the solution were addedbenzimidazole (32 mg, 0.27 mmol, 1.2 equivalents) and cesium carbonate(149 mg, 0.46 mmol, 2.0 equivalents), and the mixture was stirred at120° C. for 4 hours. The reaction mixture was partitioned with ethylacetate and water, and the resulting organic layer was washed with waterand dried over anhydrous magnesium sulfate. The organic layer wasconcentrated, to the residue was added a 4 mol/L solution of hydrogenchloride in dioxane (2 mL), and then the mixture was stirred at 100° C.for 6 hours. The reaction mixture was concentrated, then the solvent wasazeotroped with ethanol, and the residue was crystallized fromdichloromethane and diethyl ether to obtain the title compound (40 mg,42%) as a light yellow solid.

[0376] Melting point: 185-190° C. (dichloromethane/ether)

[0377]¹H-NMR (270 MHz, DMSO-d₆) δ 0.97 (t, 3H, J=7.0 Hz), 1.71-1.86 (m,8H), 2.09-2.19 (m, 2H), 3.28 (m, 1H), 3.31-3.63 (m, 2H), 4.08 (t, 2H,J=7.6 Hz), 4.37 (m, 1H), 4.53 (m, 1H), 5.18 (m, 1H), 7.55-7.66 (m, 2H),7.80-7.93 (m, 2H), 8.27 (s, 1H).

[0378] IR (CHCl₃): 1720, 1678, 1589 cm⁻¹

[0379] FAB-MS: m/z 418 (M⁺+1).

EXAMPLE 268-Chloromethyl-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 26)

[0380] Compound B1 (799 mg, 2.74 mmol) and dl-serinol (846 mg, 9.30mmol, 3.4 equivalents) were mixed and stirred at 150° C. for 4 hours. Tothe reaction mixture were added acetone (50 mL) and methanol (1 mL), andthe mixture was stirred. Crystals were collected by filtration andwashed with acetone to obtain an adduct (Compound 26a, 764 mg, 84%). ToCompound 26a (728 mg, 2.15 mmol) was added thionyl chloride (10 mL) andthe mixture was stirred with heating at 60° C. for 3.5 hours. Afterexcess thionyl chloride was evaporated, the residue was neutralized withsaturated aqueous sodium hydrogen carbonate and the mixture wasextracted with chloroform. The organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate, andthe solvent was evaporated. The residue was purified by silica gelcolumn chromatography (chloroform:methanol=95:5). To the product wasadded a 4 mol/L solution of hydrogen chloride in methanol and then themixture was concentrated. The residue was crystallized from ethylacetate and hexane to obtain the title compound (703 mg, 98%) as a whitesolid.

[0381]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.62-1.91 (m,8H), 2.00-2.13 (m, 2H), 3.17 (quin, 1H, J=7.9 Hz), 3.57 (dd, 1H, J=11.2,6.9 Hz), 3.70 (dd, 1H, J=11.2, 4.3 Hz), 4.01 (t, 2H, J=7.3 Hz), 4.03(dd, 1H, J=11.5, 3.0 Hz), 4.14 (dd, 1H, J=11.5, 9.9 Hz), 4.59 (m, 1H).

[0382] EI-MS: m/z 335 (M⁺).

EXAMPLE 272-Cyclopentyl-7,8-dihydro-8-phenylaminomethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 27)

[0383] To Compound 26 (12 mg, 0.04 mmol) obtained in Example 26 wereadded water (3 mL), aniline (20 mg, 0.24 mmol, 6.0 equivalents) andsodium hydrogen carbonate (62 mg, 0.74 mmol, 18.5 equivalents), and themixture was stirred with heating at 70° C. for 2 hours. To the reactionsolution was added water, the mixture was extracted with ethyl acetate,and the extract was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (chloroform:methanol=95:5),to the product was added a 4 mol/L solution of hydrogen chloride inethyl acetate, and then the mixture was concentrated. The residue wascrystallized from acetone and methanol to obtain the title compound (3mg, 19%) as a light yellow solid.

[0384]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.63-1.87 (m,8H), 1.99-2.11 (m, 2H), 3.15 (quin, 1H, J=7.9 Hz), 3.24 (dd, 1H, J=12.9,6.9 Hz), 3.39 (dd, 1H, J=12.9, 4.6 Hz), 3.79 (dd, 1H, J=11.2, 6.9 Hz),4.01 (t, 2H, J=7.4 Hz), 4.10 (dd, 1H, J=11.2, 9.9 Hz), 4.47 (m, 1H),6.61 (d, 2H, J=7.9 Hz), 6.71 (t, 1H, J=7.3 Hz), 7.13 (t, 2H, J=7.6 Hz).

[0385] EI-MS: m/z 392 (M⁺).

EXAMPLE 282-Cyclopentyl-7,8-dihydro-8-piperidinomethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 28)

[0386] Compound 26 (49 mg, 0.14 mmol) obtained in Example 26 wasdissolved in dimethyl sulfoxide (5 mL), to the solution was addedpiperidine (100 μL, 1.01 mmol, 7.2 equivalents), and the mixture wasstirred with heating at 80° C. for 3.5 hours. To the reaction solutionwas added water, the mixture was extracted with ethyl acetate, and theextract was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (chloroform:methanol=95:5), to theproduct was added a 4 mol/L solution of hydrogen chloride in ethylacetate, then the mixture was concentrated. The residue was crystallizedfrom acetone to obtain the title compound (31 mg, 48%) as a white solid.

[0387] Melting point: 250-255° C. (acetone)

[0388]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.20-1.30 (m,2H), 1.35-1.62 (m, 4H), 1.65-1.72 (m, 2H), 1.75-1.92 (m, 6H), 1.99-2.08(m, 2H), 2.43 (br, 5H), 2.54 (dd, 1H, J=12.5, 6.9 Hz), 3.17 (quin, 1H,J=7.6 Hz), 3.89 (dd, 1H, J=11.3, 6.3 Hz), 4.06 (t, 2H, J=7.5 Hz), 4.15(dd, 1H, J=11.2, 9.6 Hz), 4.39 (dq, 1H, J=9.6, 6.6 Hz).

[0389] IR (KBr): 1716, 1707, 1701, 1684, 1676, 1655, 1589 cm⁻¹

[0390] EI-MS: m/z 384 (M⁺).

EXAMPLE 292-Cyclopentyl-7,8-dihydro-4-(n-propyl)-8-(1-pyrrolidinylmethyl)-1H-imidazo[2,1i]purin-5(4H)-onedihydrochloride (Compound 29)

[0391] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (50 mg, 0.16 mmol) obtainedin Example 26 and pyrrolidine (100 μL, 1.20 mmol, 7.5 equivalents), andthen to the resulting product was added a 4 mol/L solution of hydrogenchloride in ethyl acetate. The reaction mixture was concentrated, andthe residue was crystallized from acetone to obtain the title compound(24 mg, 34%) as a white solid.

[0392]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.60-1.94 (m,12H), 2.00-2.08 (m, 2H), 2.56 (br, 5H), 2.74 (dd, 1H, J=12.2, 6.9 Hz),3.18 (quin, 1H, J=7.6 Hz), 3.90 (dd, 1H, J=11.2, 6.6 Hz), 4.05 (t, 2H,J=7.4 Hz), 4.16 (t, 1H, J=10.3 Hz), 4.36 (dq, 1H, J=6.6, 3.0 Hz).

[0393] EI-MS: m/z 370 (M⁺).

EXAMPLE 302-Cyclopentyl-7,8-dihydro-8-morpholinomethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 30)

[0394] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (50 mg, 0.16 mmol) obtainedin Example 26 and morpholine (100 μL, 1.14 mmol, 7.1 equivalents), andthen to the resulting product was added a 4 mol/L solution of hydrogenchloride in ethyl acetate. The mixture was concentrated and the residuewas crystallized from acetone to obtain the title compound (21 mg, 29%)as a light yellow solid.

[0395]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.61-1.91 (m,8H), 2.00-2.12 (m, 2H), 2.45 (dd, 1H, J=12.9, 7.3 Hz), 2.53 (br, 4H),2.62 (dd, 1H, J=12.9, 7.3 Hz), 3.17 (quin, 1H, J=7.6 Hz), 3.70 (br, 4H),3.88 (dd, 1H, J=11.2, 6.6 Hz), 4.02 (t, 2H, J=7.5 Hz), 4.11 (dd, 1H,J=11.2, 9.9 Hz), 4.40 (dq, 1H, J=9.6, 6.9 Hz).

[0396] EI-MS: m/z 386 (M⁺).

EXAMPLE 318-(4-Benzyl-1-piperazinylmethyl)-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onetrihydrochloride (Compound 31)

[0397] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (54 mg, 0.16 mmol) obtainedin Example 26 and 1-benzylpiperazine (100 μL, 0.58 mmol, 3.6equivalents), and then to the resulting product was added a 4 mol/Lsolution of hydrogen chloride in ethyl acetate. The mixture wasconcentrated and the residue was crystallized from acetone to obtain thetitle compound (21 mg, 23%) as a white solid.

[0398]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.59-1.93 (m,8H), 2.02-2.13 (m, 2H), 2.40-2.69 (m, 10H), 3.19 (quin, 1H, J=7.8 Hz),3.49 (s, 2H), 3.88 (dd, 1H, J=11.3, 6.3 Hz), 4.05 (t, 2H, J=7.3 Hz),4.14 (dd, 1H, J=11.3, 9.9 Hz), 4.39 (m, 1H), 7.24-7.39 (m, 5H).

[0399] EI-MS: m/z 475 (M⁺).

EXAMPLE 322-Cyclopentyl-7,8-dihydro-8-(4-phenyl-1-piperazinylmethyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onetrihydrochloride (Compound 32)

[0400] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (53 mg, 0.16 mmol) obtainedin Example 26 and 1-phenylpiperazine (100 μL, 0.65 mmol, 4.1equivalents), and to the resulting product was added a 4 mol/L solutionof hydrogen chloride in ethyl acetate. The mixture was concentrated andthe residue was crystallized from methanol and acetone to obtain thetitle compound (33 mg, 37%) as a white solid.

[0401] Melting point: 190-195° C. (methanol/acetone)

[0402]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.58-1.89 (m,8H), 1.99-2.09 (m, 2H), 2.51 (dd, 1H, J=12.9, 6.9 Hz), 2.66 (dd, 1H,J=12.9, 5.9 Hz), 2.55-2.75 (m, 4H), 3.18 (br, 5H), 3.91 (dd, 1H, J=12.2,6.3 Hz), 4.03 (t, 2H, J=7.4 Hz), 4.14 (dd, 1H, J=12.2, 9.9 Hz), 4.43 (m,1H), 6.85 (d, 1H, J=7.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.27 (dd, 2H,J=8.8, 7.3 Hz).

[0403] IR (KBr): 1722, 1709, 1693, 1664, 1587, 1558, 1508 cm⁻¹

[0404] EI-MS: m/z 461 (M⁺).

[0405] Elemental Analysis for C₂₆H₃₅N₇O.3.0 HCl.1.0H₂O.0.1C₃H₆O

[0406] Calculated(%): C, 53.11; H, 6.88; N, 16.48.

[0407] Found (%): C, 53.08; H, 6.95; N, 16.52.

EXAMPLE 338-(4-Benzylpiperidinomethyl)-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-oneDihydrochloride (Compound 33)

[0408] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (53 mg, 0.16 mmol) obtainedin Example 26 and 4-benzylpiperidine (100 μL, 0.59 mmol, 3.7equivalents), and then to the resulting product was added a 4 mol/Lsolution of hydrogen chloride in ethyl acetate. The mixture wasconcentrated and the residue was crystallized from acetone to obtain thetitle compound (41 mg, 48%) as a white solid.

[0409]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.4 Hz), 1.25 (m, 2H),1.40-2.15 (m, 14H), 2.40 (dd, 1H, J=11.5, 6.9 Hz), 2.51 (d, 2H, J=6.6Hz), 2.56 (dd, 1H, J=11.5, 7.4 Hz), 2.85 (d, 2H, J=11.2 Hz), 3.18 (quin,1H, J=8.2 Hz), 3.87 (dd, 1H, J=11.2, 6.2 Hz), 4.05 (t, 2H, J=7.6 Hz),4.12 (dd, 1H, J=11.2, 9.5 Hz), 4.36 (quin, 1H, J=6.6 Hz), 7.13 (d, 2H,J=8.2 Hz), 7.20-7.34 (m, 3H).

[0410] EI-MS: m/z 474 (M⁺).

EXAMPLE 348-Benzylaminomethyl-2-cyclopentyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onedihydrochloride (Compound 34)

[0411] In a manner similar to that in Example 28, the title compound inthe free form was obtained from Compound 26 (40 mg, 0.12 mmol) obtainedin Example 26 and benzylamine (100 μL, 0.91 mmol, 7.6 equivalents), andthen to the resulting product was added a 4 mol/L solution of hydrogenchloride in ethyl acetate. The mixture was concentrated and the residuewas crystallized from acetone to obtain the title compound (9 mg, 16%)as a white solid.

[0412] Melting point: 225-235° C. (acetone)

[0413]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.4 Hz), 1.57-1.91 (m,8H), 1.97-2.12 (m, 2H), 2.74 (dd, 1H, J=12.1, 6.9 Hz), 2.86 (dd, 1H,J=12.1, 4.9 Hz), 3.15 (quin, 1H, J=7.3 Hz), 3.79 (dd, 1H, J=10.8, 3.3Hz), 3.82 (d, 2H, J=4.6 Hz), 4.00 (t, 2H, J=7.6 Hz), 4.06 (dd, 1H,J=10.8, 9.9 Hz), 4.37 (m, 1H), 7.21 (m, 5H).

[0414] IR (KBr): 1718, 1674, 1655, 1516, 1508, 1458, 1394, 1363 cm⁻¹

[0415] EI-MS: m/z 406 (M⁺).

EXAMPLE 35(R)-1,8-Dibenzyl-2-bromo-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 35)

[0416] To Compound 13a (6.65 g, 21.2 mmol) obtained in Example 13 wasadded (R)-phenylalaminol (4.80 g, 31.7 mmol, 1.5 equivalents) and themixture was stirred with heating at 150° C. for 4 hours. The reactionmixture was directly purified by silica gel column chromatography(chloroform:methanol=100:1 to 100:3) to obtain an adduct (2.66 g, 30%).To the resulting adduct (2.66 g, 6.37 mmol) was added thionyl chloride(5 mL) and the mixture was stirred with heating at 60° C. for 2.5 hours.After the thionyl chloride was evaporated, the residue was neutralizedwith saturated aqueous sodium hydrogen carbonate and the mixture wasextracted with chloroform. The organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=100:1) to obtain(R)-1,8-dibenzyl-7,8-dihydro-4-(n-propyl)-1Himidazo[2,1-i]purin-5(4H)-one(Compound 35a, 1.75 g, 69%). Compound 35a (1.75 g, 4.38 mmol) wasdissolved in tetrahydrofuran (30 mL), to the solution was added a 1.54mol/L solution of lithium diisopropylamide (4.38 mL, 6.75 mmol, 1.5equivalents) in cyclohexane at −78° C., and the mixture was stirred for1 hour. To the reaction solution was added a solution (10 mL) of carbontetrabromide (2.18 g, 6.65 mmol, 1.5 equivalents) in tetrahydrofuran,and the mixture was stirred at −78° C. for 1 hour, then warmed to roomtemperature and stirred for 2 hours. To the reaction solution was addedsaturated aqueous ammonium chloride and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, and the solventwas evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=99.5:0.5), the eluent wasconcentrated, and to the residue were added acetone and diethyl ether.The deposited crystals were collected by filtration and dried underreduced pressure to obtain the title compound (1.51 g, 72%) as whitecrystals.

[0417] Melting point: 200-206° C. (acetone/diethyl ether)

[0418]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.6 Hz), 1.72 (q, 2H,J=7.6 Hz), 2.75 (dd, 1H, J=13.6, 8.3 Hz), 3.10 (dd, 1H, J=13.6, 5.7 Hz),3.64 (dd, 1H, J=11.2, 6.9 Hz), 3.84 (dd, 1H, J=11.2, 9.9 Hz), 3.88 (t,2H, J=7.6 Hz), 4.55 (m, 1H), 5.46 (d, 1H, J=15.2 Hz), 5.53 (d, 1H,J=15.2 Hz), 7.17-7.30 (m, 6H), 7.33-7.42 (m, 4H).

[0419] IR (KBr): 1693, 1682, 1666, 1655, 1587, 1520, 1441, 1367 cm⁻¹

[0420] EI-MS: m/z 478 (M⁺+1).

[0421] Elemental Analysis for C₂₄H₂₄BrN₅O.0.3H₂O

[0422] Calculated(%): C, 59.58; H, 5.12; N, 14.48.

[0423] Found (%): C, 59.59; H, 4.98; N, 14.21.

EXAMPLE 36(R)-8-Benzyl-7,8-dihydro-1-methoxymethyl-2-methylthio-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 36)

[0424] 6-Methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B8, 11.8g, 52.5 mmol), which was obtained by the method described in Journal ofHeterocyclic Chemistry (J. Heterocycl. Chem.), 30, p.241, 1993, wasdissolved in N,N-dimethylformamide (200 mL). To the solution was addedsodium hydride (1.51 g, 63.0 mmol, 1.2 equivalents) and the mixture wasstirred at room temperature for 30 minutes. To the reaction solution wasadded chloromethyl methyl ether (4.85 mL, 63.9 mmol, 1.2 equivalents)and the mixture was stirred at room temperature for 1 hour. To thereaction solution was added saturated aqueous ammonium chloride, themixture was extracted with chloroform, and the organic layer was washedwith saturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. Then, the solvent was evaporated, and to the resulting residuewas added diethyl ether. The deposited crystals were collected byfiltration to obtain a methoxymethyl adduct.(R)-8-Benzyl-2-bromo-7,8-dihydro-1-methoxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 36a, 2.81 g, 6.52 mmol), which was obtained from themethoxymethyl adduct in a manner similar to that in Example 35, wasdissolved in N,N-dimethylformamide (26 mL), to the solution was added anabout 15% aqueous solution of methylmercaptan sodium salt (6.10 mL, 13.1mmol, 2.0 equivalents), and the mixture was stirred at room temperaturefor three days. To the reaction solution was added water, the mixturewas extracted with chloroform, then the organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The reaction residue waspurified by silica gel column chromatography (chloroform:methanol=98:2)and the eluent was concentrated. To the residue was added acetonitrile,and the deposited crystals were collected by filtration to obtain thetitle compound (2.17 g, 84%) as white crystals.

[0425] Melting point: 110-112° C. (acetonitrile)

[0426]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.3 Hz), 1.74 (q, 2H,J=7.3 Hz), 2.68 (s, 3H), 2.71 (dd, 1H, J=13.6, 8.6 Hz), 3.14 (dd, 1H,J=13.6, 5.3 Hz), 3.43 (s, 3H), 3.64 (dd, 1H, J=11.2, 6.9 Hz), 3.81 (dd,1H, J=11.2, 9.9 Hz), 3.93 (t, 2H, J=7.3 Hz), 4.55 (m, 1H), 5.53 (d, 1H,J=10.6 Hz), 5.60 (d, 1H, J=10.6 Hz), 7.18-7.31 (m, 5H).

[0427] IR (KBr): 1714, 1693, 1648, 1560, 1541, 1516, 1389, 1320, 1122cm⁻¹

[0428] EI-MS: m/z 400 (M⁺+1).

[0429] Elemental Analysis for C₂₀H₂₅N₅O₂S

[0430] Calculated(%): C, 60.13; H, 6.31; N, 17.53.

[0431] Found (%): C, 59.95; H, 6.38; N, 17.44.

EXAMPLE 37(R)-1,8-Dibenzyl-7,8-dihydro-4-(n-propyl)-2-(1-pyrrolidinyl)imidazo-[2,1-i]purin-5(4H)-one(Compound 37)

[0432] Compound 35 (500 mg, 1.05 mmol) obtained in Example 35 wasdissolved in N,N-dimethylformamide (15 mL), to the solution were addedpotassium carbonate (430 mg, 3.11 mmol, 3.0 equivalents) and pyrrolidine(260 p L, 3.11 mmol, 3.0 equivalents), and then the mixture was stirredwith heating at 100° C. for 3.5 hours. To the reaction solution wasadded water, the mixture was extracted with ethyl acetate, and theextract was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (chloroform:methanol=99:1 to 97:3), andto the residue were added acetone and diethyl ether. The depositedcrystals were collected by filtration to obtain the title compound (467mg, 95%) as white crystals.

[0433] Melting point: 124-125° C. (acetone/diethyl ether)

[0434]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.3 Hz), 1.74 (q, 2H,J=7.3 Hz), 1.87 (quin, 4H, J=3.3 Hz), 2.66 (dd, 1H, J=13.6, 8.3 Hz),3.04 (dd, 1H, J=13.6, 5.3 Hz), 3.46 (t, 4H, J=6.6 Hz), 3.60 (dd, 1H,J=10.9, 6.6 Hz), 3.76 (dd, 1H, J=10.9, 9.9 Hz), 3.88 (t, 2H, J=7.3 Hz),4.46 (m, 1H), 5.45 (d, 1H, J=16.8 Hz), 5.57 (d, 1H, J=16.8 Hz),7.10-7.36 (m, 10H).

[0435] IR (KBr): 1687, 1660, 1604, 1549, 1510, 1491, 1454, 1404, 1354,1259 cm⁻¹

[0436] EI-MS: m/z 469 (M⁺+1).

[0437] Elemental Analysis for C₂₈H₃₂N₆O.0.3H₂O

[0438] Calculated(%): C, 70.95; H, 6.93; N, 17.73.

[0439] Found (%): C, 70.97; H, 7.07; N, 17.81.

EXAMPLE 38(R)-8-Benzyl-7,8-dihydro-4-(n-propyl)-2-(11-pyrrolidinyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 38)

[0440] Compound 37 (329 mg, 7.03 mmol) obtained in Example 37 wasdissolved in methanol (5 mL), to the solution were added ammoniumformate (950 mg, 15.0 mmol, 2.0 equivalents) and 20% palladiumhydroxide/carbon (50 mg), and then the mixture was stirred under refluxwith heating for 3 hours. The reaction mixture was filtered by usingCelite and then concentrated, and the residue was purified by silica gelcolumn chromatography (chloroform:methanol=90:10). The solvent wasevaporated, then to the residue were added a 4 mol/L solution (4 mL) ofhydrogen chloride in dioxane and methanol (4 mL), and the mixture wasconcentrated. The residue was crystallized from acetone and diethylether to obtain the title compound (75 mg, 28%) as white crystals.

[0441] Melting point: 248-250° C. (acetone/diethyl ether)

[0442]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.3 Hz), 1.75 (q, 2H,J=7.3 Hz), 2.03-2.08 (m, 4H), 2.94 (dd, 1H, J=13.8, 7.9 Hz), 3.19 (dd,1H, J=13.8, 4.6 Hz), 3.63 (t, 4H, J=6.6 Hz), 3.99 (dd, 1H, J=11.5, 6.9Hz), 4.00 (t, 2H, J=7.3 Hz), 4.12 (dd, 1H, J=11.5, 9.2 Hz), 4.57 (m,1H), 7.24-7.36 (m, 5H), 9.88 (brs, 1H).

[0443] IR (KBr): 1714, 1680, 1628, 1568, 1518, 1458, 1441, 1396, 1348,1300 cm⁻¹

[0444] EI-MS: m/z 379 (M⁺+1).

[0445] Elemental Analysis for C₂₁H₂₆N₆O.HCl.0.3H₂O

[0446] Calculated(%): C, 60.01; H, 6.62; N, 19.99.

[0447] Found (%): C, 60.07; H, 6.73; N, 20.09.

EXAMPLE 39(R)-8-Benzyl-7,8-dihydro-2-morpholino-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 39)

[0448] In a manner similar to that in Example 37, an adduct was obtainedfrom Compound 36a (100 mg, 0.23 mmol) obtained in Example 36 andmorpholine (120 μL, 1.38 mmol, 6.0 equivalents). To the resulting adductwere added a 4 mol/L solution (5 mL) of hydrogen chloride in dioxane andmethanol (5 mL), and then the mixture was stirred under reflux withheating for 2 hours. The reaction mixture was concentrated, and theresidue was crystallized from acetone and diethyl ether to obtain thetitle compound (33 mg, 32%) as white crystals.

[0449]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.3 Hz), 1.74 (q, 2H,J=7.3 Hz), 2.94 (dd, 1H, J=13.8, 7.9 Hz), 3.18 (dd, 1H, J=13.8, 4.6 Hz),3.62 (m, 4H), 3.79 (m, 4H), 3.97 (dd, 1H, J=11.6, 6.6 Hz), 3.98 (t, 2H,J=7.4 Hz), 4.11 (dd, 1H, J=11.6, 9.3 Hz), 4.56 (m, 1H), 7.18-7.34 (m,5H), 9.87 (brs, 1H).

[0450] EI-MS: m/z 394 (M⁺).

EXAMPLE 40(R)-8-Benzyl-7,8-dihydro-2-(1-hydroxycyclopentyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 40)

[0451] Compound 35a (9.28 g, 24.1 mmol) obtained in Example 35 wasdissolved in tetrahydrofuran (200 mL), to the solution was added a 1.48mol/L solution of lithium diisopropylamide (73.0 mL, 34.8 mmol, 1.5equivalents) in cyclohexane at −78° C., and the mixture was stirred for1 hour. To the reaction solution was added a solution (20 mL) ofcyclopentanone (3.80 g, 45.2 mmol, 1.9 equivalents) in tetrahydrofuran,and the mixture was stirred at −78° C. for 1 hour, then warmed to roomtemperature and stirred for 20 hours. To the reaction solution was addedsaturated aqueous ammonium chloride and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate, and the solvent wasevaporated. The residue was purified by silica gel column chromatography(ethyl acetate) to obtain an adduct (3.32 g, 30%). The resulting adduct,i.e., Adduct 40a (3.04 g, 6.29 mmol), was dissolved in methanol (100mL), to the solution were added ammonium formate (1.18 g, 18.7 mmol, 3.0equivalents) and 20% palladium hydroxide/carbon (600 mg), and themixture was stirred under reflux with heating for 3 hours. The reactionmixture was filtered by using Celite and concentrated, and the residuewas purified by silica gel column chromatography(chloroform:methanol=99:1). After the solvent was evaporated, theresidue was crystallized from ethyl acetate to obtain the title compound(2.22 g, 90%) as white crystals.

[0452] Melting point: 110-115° C. (ethyl acetate)

[0453]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.4 Hz), 1.73-2.04 (m,8H), 2.15-2.36 (m, 2H), 2.80 (dd, 1H, J=13.4, 6.3 Hz), 2.88 (dd, 1H,J=13.4, 7.1 Hz), 3.73 (dd, 1H, J=10.4, 6.0 Hz), 3.93-4.16 (m, 4H),7.10-7.29 (m, 5H).

[0454] IR (KBr): 1695, 1653, 1541, 1497, 1454, 1265 cm⁻¹

[0455] EI-MS: m/z 394 (M⁺+1).

[0456] Elemental Analysis for C₂₂H₂₇N₅O₂.0.1H₂O

[0457] Calculated(%): C, 66.85; H, 6.94; N, 17.72.

[0458] Found (%): C, 66.83; H, 7.23; N, 17.54.

EXAMPLE 41(R)-1,8-Dibenzyl-2-formyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 41)

[0459] Compound 35a (3.45 g, 8.96 mmol) obtained in Example 35 wasdissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50mol/L solution (9.0 mL) of lithium diisopropylamide (13.5 mmol, 1.5equivalents) in cyclohexane at −78° C., and the mixture was stirred for1 hour. To the reaction solution was added a solution (10 mL) ofN,N-dimethylformamide (2.83 g, 38.7 mmol, 4.3 equivalents) intetrahydrofuran, and the mixture was stirred at −78° C. for 1 hour, thenwarmed to room temperature and stirred for 1 hour. To the reactionsolution was added saturated aqueous ammonium chloride and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=33:67 to50:50). To the residue was added ethyl acetate, and the depositedcrystals were collected by filtration to obtain the title compound (3.31g, 89%) as white crystals.

[0460] Melting point: 184-185° C. (ethyl acetate)

[0461]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.6 Hz), 1.75 (q, 2H,J=7.6 Hz), 2.79 (dd, 1H, J=13.5, 7.9 Hz), 3.15 (dd, 1H, J=13.5, 5.6 Hz),3.67 (dd, 1H, J=11.3, 7.3 Hz), 3.84-3.96 (m, 3H), 4.64 (m, 1H), 5.91 (d,1H, J=14.2 Hz), 6.01 (d, 1H, J=14.2 Hz), 7.18-7.46 (m, 10H), 9.81 (s,1H).

[0462] IR (KBr): 1718, 1703, 1693, 1660, 1649, 1572, 1560, 1543, 1467,1344 cm⁻¹

[0463] EI-MS: m/z 428 (M⁺+1).

[0464] Elemental Analysis for C₂₅H₂₅N₅O₂.0.4H₂O

[0465] Calculated(%): C, 69.07; H, 5.98; N, 16.11.

[0466] Found (%): C, 69.09; H, 5.89; N, 15.94.

EXAMPLE 42(R)-1,8-Dibenzyl-2-chloromethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 42)

[0467] Compound 41 (2.71 g, 6.55 mmol) obtained in Example 41 wasdissolved in dichloromethane (25 mL) and ethanol (50 mL), to thesolution was added sodium borohydride (2.48 g, 65.6 mmol, 1.0equivalent), and the mixture was stirred at room temperature for 3hours. To the reaction solution was added saturated aqueous ammoniumchloride and the mixture was extracted with chloroform. The organiclayer was washed with saturated aqueous sodium chloride and dried, andthen the solvent was evaporated to obtain an alcohol compound (1.76 g).To the alcohol compound was added thionyl chloride (10.0 mL, 51.5 mmol)and the mixture was stirred at 60° C. for 2 hours. The reaction solutionwas concentrated, then to the residue was added saturated aqueous sodiumhydrogen carbonate, and the mixture was extracted with chloroform. Theorganic layer was washed with saturated aqueous sodium chloride anddried over anhydrous sodium sulfate, and then the solvent wasevaporated. The residue was purified by silica gel column chromatography(chloroform:methanol=99.5:0.5), and to the residue was added acetone anddiethyl ether. The deposited crystals were collected by filtration toobtain the title compound (1.45 g, 49%) as white crystals.

[0468] Melting point: 112-113° C. (acetone/diethyl ether)

[0469]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.74 (q, 2H,J=7.3 Hz), 2.73 (dd, 1H, J=13.5, 8.2 Hz), 3.10 (dd, 1H, J=13.5, 5.3 Hz),3.66 (dd, 1H, J=10.9, 6.6 Hz), 3.84 (dd, 1H, J=10.9, 9.9 Hz), 3.90 (t,2H, J=7.3 Hz), 4.47 (s, 2H), 4.56 (m, 1H), 5.64 (d, 1H, J=15.8 Hz), 5.68(d, 1H, J=15.8 Hz), 7.16-7.41 (m, 10H).

[0470] IR (KBr): 1684, 1672, 1581, 1525, 1454, 1425, 1392, 1336, 1265,743 cm⁻¹

[0471] EI-MS: m/z 447 (M⁺).

[0472] Elemental Analysis for C₂₅H₂₆ClN₅O.0.2H₂O

[0473] Calculated(%): C, 66.50; H, 5.89; N, 15.51.

[0474] Found (%): C, 66.51; H, 5.84; N, 15.39.

EXAMPLE 43(R)-8-Benzyl-2-dimethylaminomethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 43)

[0475] Compound 42 (60 mg, 0.134 mmol) obtained in Example 42 wasdissolved in tetrahydrofuran (3 mL), to the solution was added a 2 mol/Lsolution of dimethylamine (200 μL, 0.401 mmol, 3.1 equivalents) intetrahydrofuran, and the mixture was stirred with heating at 70° C. for5.5 hours. The reaction solution was concentrated and then directlypurified by silica gel column chromatography (chloroform:methanol=99:1to 97:3), and the title compound (7 mg, 19%) was obtained in a mannersimilar to the method by which Compound 40 was obtained from Adduct 40ain Example 40.

[0476]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.81 (q, 2H,J=7.3 Hz), 2.30 (s, 6H), 2.87-2.91 (m, 2H), 3.57 (d, 1H, J=14.2 Hz),3.64 (d, 1H, J=14.2 Hz), 3.79 (dd, 1H, J=13.3, 6.6 Hz), 4.02 (dd, 1H,J=13.9, 9.9 Hz), 4.06 (t, 2H, J=7.3 Hz), 4.17 (m, 1H), 7.12-7.20 (m,5H).

[0477] EI-MS: m/z 366 (M⁺).

EXAMPLE 44(R)-8-Benzyl-7,8-dihydro-2-piperidinomethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 44)

[0478] In a manner similar to that in Example 43, the title compound (18mg, 33%) was obtained from Compound 42 (60 mg, 0.134 mmol) obtained inExample 42 and piperidine (100 μL, 1.01 mmol, 7.8 equivalents).

[0479]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.42-1.55(m,2H), 1.62-1.70 (m, 4H), 1.82 (q, 2H, J=7.3 Hz), 2.55-2.57 (m, 4H),2.92 (dd, 1H, J=13.6, 6.6 Hz), 3.08 (dd, 1H, J=13.6, 7.0 Hz), 3.73 (s,2H), 3.88 (dd, 1H, J=13.6, 7.0 Hz), 4.02-4.13 (m, 3H), 4.43 (m, 1H),7.19-7.32 (m, 5H).

[0480] EI-MS: m/z 406 (M⁺).

EXAMPLE 45(R)-8-Benzyl-2-ethoxymethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 45)

[0481] Compound B12 (20.0 g, 70.8 mmol) obtained in Reference Example 22and (R)-phenylalaminol (16.1 g, 106 mmol, 1.5 equivalents) were stirredat 150° C. for 5 hours. The resulting reaction mixture was directlypurified by silica gel column chromatography (chloroform:methanol=99:1to 95:5) to obtain an adduct (27.1 g, 99%). To the resulting adduct(27.1 g, 70.3 mmol) was added thionyl chloride (50 mL, 685 mmol, 9.7equivalents) and the mixture was stirred at 60° C. for 1 hour. Excessthionyl chloride was evaporated, to the resulting residue were addedchloroform and saturated aqueous sodium hydrogen carbonate, and then themixture was stirred at room temperature for 1 hour. The reaction mixturewas extracted with chloroform, then the organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform:methanol=99.5:0.5) toobtain the title compound in the free form (Compound 45a, 22.8 g, 88%).To a solution of Compound 45a (22.8 g, 61.9 mmol) in methanol (100 mL)was added fumaric acid (3.47 g, 29.9 mmol, 0.5 equivalent), and thesolvent was evaporated. To the residue were added acetone and diethylether, and the deposited crystals were collected by filtration to obtainthe title compound (18.0 g, 60%) as white crystals.

[0482] Further, the title compound in the free form (Compound 45a) wasalso obtained by the following method. Compound 42 (60 mg, 0.134 mmol)obtained in Example 42 was dissolved in ethanol (2 mL), to the solutionwas added a 21% solution of sodium ethoxide (100 μL, 0.312 mmol, 2.4equivalents) in ethanol, and the mixture was stirred with heating at 70°C. for 3 hours. The reaction solution was concentrated and then directlypurified by silica gel column chromatography (chloroform:methanol=99:1to 97:3). Then the title compound in the free form (Compound 45a, 18 mg,36%) was obtained in a manner similar to the method by which Compound 40was obtained from Adduct 40a in Example 40.

[0483] Melting point: 168-170° C. (acetone/diethyl ether)

[0484]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.33 (t, 3H,J=6.9 Hz), 1.78 (q, 2H, J=7.3 Hz), 3.00 (dd, 1H, J=13.8, 7.9 Hz), 3.21(dd, 1H, J=13.8, 4.9 Hz), 3.69 (q, 2H, J=6.9 Hz), 4.03 (dd, 1H, J=11.9,6.6 Hz), 4.06 (t, 2H, J=6.6 Hz), 4.18 (dd, 1H, J=11.9, 9.6 Hz), 4.69 (s,2H), 4.70 (m, 1H), 6.88 (s, 2H), 7.18-7.36(m, 5H), 8.48 (br, 1H).

[0485] IR (KBr) 1708, 1691, 1637, 1541, 1456, 1379, 1299 cm⁻¹

[0486] EI-MS: m/z 368 (M⁺+1).

[0487] Elemental Analysis for C₂₀H₂₅N₅O₂.0.5C₄H₄O₄.0.1H₂O

[0488] Calculated(%): C, 61.84; H, 6.42; N, 16.39.

[0489] Found (%): C, 61.92; H, 6.49; N, 16.53.

EXAMPLE 46(R)-8-Benzyl-2-[(4R,5R)-dimethyl-1,3-dioxacyclopentan-2-yl]-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 46)

[0490] Compound 41 (150 mg, 0.351 mmol) obtained in Example 41 wasdissolved in toluene (25 mL), to the solution were added(2R,3R)-butanediol (100 mg, 1.11 mmol, 3.2 equivalents) andp-toluenesulfonic acid monohydrate (70 mg, 0.368 mmol, 1.0 equivalent),and then the mixture was refluxed with heating for 3.5 hours. To thereaction solution was added saturated aqueous sodium hydrogen carbonate,the mixture was extracted with chloroform, and the organic layer waswashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent was evaporated to obtain an adduct (156 mg,0.313 mmol), from which the title compound (48 mg, 33%) was obtained aswhite crystals in a manner similar to the method by which Compound 40was obtained from Adduct 40a in Example 40.

[0491] Melting point: 169-170° C. (acetone)

[0492]¹H-NMR (270 MHz, CDCl₃) δ 0.99 (t, 3H, J=7.6 Hz), 1.31 (d, 3H,J=5.9 Hz), 1.34 (d, 3H, J=5.9 Hz), 1.89 (q, 2H, J=7.6 Hz), 2.83-2.87 (m,2H), 3.79 (dq, 1H, J=7.9, 5.9 Hz), 3.86-3.95 (m, 2H), 4.09-4.19 (m, 3H),4.46 (m, 1H), 6.07 (s, 1H), 7.09-7.19 (m, 5H).

[0493] IR (KBr) 1711, 1689, 1670, 1648, 1548, 1456, 1273 cm⁻¹

[0494] EI-MS: m/z 410 (M⁺+1).

[0495] Elemental Analysis for C₂₂H₂₇N₅O₃.0.2H₂O

[0496] Calculated(%): C, 63.97; H, 6.69; N, 16.95.

[0497] Found (%): C, 63.92; H, 6.73; N, 17.11.

EXAMPLE 47(R)-1,8-Dibenzyl-7,8-dihydro-2-methoxycarbonyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 47)

[0498] Compound 35a (3.95 g, 9.90 mmol) obtained in Example 35 wasdissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50mol/L solution (9.9 mL) of lithium diisopropylamide (14.9 mmol, 1.5equivalents) in cyclohexane at −78° C., and then the mixture was stirredfor 1 hour. Into the reaction solution was poured carbon dioxidegenerated from dry ice and the mixture was stirred at room temperaturefor 1 hour. To the reaction solution was added 1 mol/L aqueoushydrochloric acid and the mixture was extracted with chloroform. Theorganic layer was washed with saturated aqueous sodium chloride anddried. The solvent was evaporated, and the residue was purified bysilica gel column chromatography (chloroform:methanol=95:5 to 10:1). Tothe residue were added acetone and diethyl ether, and the depositedcrystals were collected by filtration to obtain(R)-1,8-dibenzyl-2-carboxy-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 47a, 1.13 g, 26%). To Compound 47a (740 mg, 1.67 mmol) wasadded thionyl chloride (10.0 mL, 137 mmol, 82 equivalents) and themixture was stirred at 60° C. for 2 hours. The reaction solution wasconcentrated under reduced pressure, and then to the reaction residuewas added methanol (3 mL). The mixture was concentrated and the residuewas directly purified by silica gel column chromatography(chloroform:methanol=95:5) to obtain the title compound (211 mg, 28%).

[0499]¹H-NMR (270 MHz, CDCl₃) δ 0.94 (t, 3H, J=7.3 Hz), 1.74 (q, 2H,J=7.3 Hz), 2.77 (dd, 1H, J=13.7, 7.8 Hz), 3.06 (dd, 1H, J=13.7, 5.4 Hz),3.67 (dd, 1H, J=11.1, 7.0 Hz), 3.87 (dd, 1H, J=11.1, 10.0 Hz), 3.92-3.99(m, 5H), 4.61 (m, 1H), 6.01 (d, 1H, J=14.8 Hz), 6.09 (d, 1H, J=14.8 Hz),7.16-7.35 (m, 10H).

[0500] EI-MS: m/z 458 (M⁺+1).

EXAMPLE 48(R)-1,8-Dibenzyl-7,8-dihydro-2-(2-hydroxypropan-2-yl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 48)

[0501] Compound 47 (100 mg, 0.218 mmol) obtained in Example 47 wasdissolved in tetrahydrofuran (5 mL), to the solution was added a 3.0mol/L solution (500 μL) of methyl magnesium bromide (1.50 mmol, 6.8equivalents) in diethyl ether, and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure and then the residue was directly purified by silicagel column chromatography (chloroform:methanol=95:5) to obtain the titlecompound (60 mg, 60%).

[0502]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.3 Hz), 1.51 (s, 3H),1.52 (s, 3H), 1.74 (q, 2H, J=7.3 Hz), 2.62 (dd, 1H, J=13.5, 7.9 Hz),2.95 (dd, 1H, J=13.5, 5.6 Hz), 3.60 (dd, 1H, J=11.2, 6.9 Hz), 3.77 (dd,1H, J=11.2, 9.9 Hz), 3.91 (t, 2H, J=7.3 Hz), 4.45 (m, 1H), 5.82 (d, 1H,J=16.2 Hz), 5.89 (d, 1H, J=16.2 Hz), 7.03-7.37 (m, 10H).

[0503] EI-MS: m/z 458 (M⁺+1).

EXAMPLE 49(R)-8-Benzyl-7,8-dihydro-2-piperidinocarbonyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 49)

[0504] Compound 47a (70 mg, 0.158 mmol) obtained in Example 47 wasdissolved in chloroform (2 mL), to the solution was added thionylchloride (40 μL, 0.548 mmol, 3.4 equivalents), and the mixture wasstirred at 60° C. for 30 minutes. To the reaction solution was addedpiperidine (320 μL, 3.24 mmol, 20 equivalents) and the mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated and directly purified by silica gel column chromatography(chloroform:methanol=98:2). Thereafter, the title compound (17 mg, 26%)was obtained in a manner similar to the method by which Compound 40 wasobtained from Adduct 40a in Example 40.

[0505]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.4 Hz), 1.50-1.75 (m,6H), 1.82 (q, 2H, J=7.4 Hz), 2.78 (dd, 1H, J=13.7, 5.5 Hz), 3.06 (dd,1H, J=13.7, 5.1 Hz), 3.67-4.19 (m, 8H), 5.05 (m, 1H), 7.14-7.27 (m, 5H).

[0506] EI-MS: m/z 421 (M⁺+1).

EXAMPLE 50(R)-8-Benzyl-7,8-dihydro-2-morpholinocarbonyl-4-(n-propyl)-1H-imidzole[2,1-i]purin-5(4H)-one(Compound 50)

[0507] In a manner similar to that in Example 49, the title compound (15mg, 9%) was obtained from Compound 47a (50 mg, 0.113 mmol) obtained inExample 47 and morpholine (100 μL, 1.15 mmol, 10 equivalents).

[0508]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.82 (q, 2H,J=7.3 Hz), 2.81 (dd, 1H, J=13.2, 7.9 Hz), 3.03 (dd, 1H, J=13.2, 5.6 Hz),3.67-3.96 (m, 4H), 3.98-4.25 (m, 8H), 5.04 (m, 1H), 7.10-7.18 (m, 5H).

[0509] EI-MS: m/z 423 (M⁺+1).

EXAMPLE 51(R)-8-Benzyl-7,8-dihydro-4-(n-propyl)-2-(tetrahydrofuran-2-yl)-1H-imidazo[2,1i]purin-5(4H)-oneD-tartrate (Compound 51)

[0510] In a manner similar to that in Example 45, an adduct (1.38 g,99%) was obtained from Compound B13 (1.00 g, 3.40 mmol) prepared inReference Example 23 and (R)-phenylalaminol (770 mg, 5.10 mmol, 1.5equivalents). To a solution of the adduct (1.00 g, 2.52 mmol) inmethylene chloride (10 mL) was added methanesulfonyl chloride (390 μL,5.01 mmol, 2.0 equivalents) and pyridine (200 μL, 2.50 mmol, 1.0equivalent) and the mixture was stirred at room temperature for 20hours. To the reaction solution were further added methanesulfonylchloride (390 μL, 5.01 mmol, 2.0 equivalents) and pyridine (200 μL) andthe mixture was stirred for 24 hours. The reaction mixture wasconcentrated, to the resulting residue was added saturated aqueoussodium hydrogen carbonate, and the mixture was stirred for 1 hour. Thereaction mixture was extracted with chloroform, and the resultingorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was purified by silica gel columnchromatography (chloroform:methanol=99:1) to obtain the title compoundin the free form. To a methanol solution of the title compound in thefree form was added D-tartaric acid for salt formation to obtain thetitle compound (250 mg, 5%).

[0511] Melting point: 148-149° C. (methanol)

[0512]¹H-NMR (270 MHz, CDCl₃) δ 0.94-0.99 (m, 3H), 1.72-1.81 (m, 2H),2.00-2.18 (m, 3H), 2.40 (m, 1H), 3.02 (m, 1H), 3.21 (m, 1H), 3.92-4.24(m, 6H), 4.45 (s, 2H), 4.76 (m, 1H), 5.13 (dd, 1H, J=7.9, 5.6 Hz),7.23-7.31 (m, 5H).

[0513] IR (KBr) 1734, 1720, 1711, 1703, 1670 cm⁻¹

[0514] TOF-MS: m/z 380 (M⁺+1).

EXAMPLE 52*R)-8-Benzyl-2-(1-ethoxyethyl)-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 52)

[0515] In a manner similar to that in Example 45, the title compound inthe free form was obtained from Compound B14 (500 mg, 1.69 mmol)prepared in Reference Example 24 and (R)-phenylalaminol (380 mg, 2.51mmol, 1.5 equivalents), and it was subjected to salt formation withfumaric acid to obtain the title compound (77 mg, 4%) as white crystals.

[0516] Melting point: 165-170° C. (ethyl acetate/n-hexane)

[0517]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.3 Hz), 1.28 (t, 3H,J=6.9 Hz), 1.60 (d, 3H, J=6.6 Hz), 1.77 (q, 2H, J=7.3 Hz), 2.98 (dd, 1H,J=13.9, 7.9 Hz), 3.23 (brd, 1H, J=13.9 Hz), 3.57 (q, 2H, J=6.9 Hz), 4.00(dd, 1H, J=11.9, 6.9 Hz), 4.07 (t, 2H, J=7.3 Hz), 4.14 (t, 1H, J=11.8Hz), 4.67 (q, 1H, J=6.9 Hz), 6.91 (s, 2H), 7.23-7.32 (m, 5H).

[0518] IR (KBr) 1738, 1716, 1699, 1687, 1674, 1651, 1583, 1367, 1271cm⁻¹

[0519] EI-MS: m/z 382 (M⁺+1).

[0520] Elemental Analysis for C₂₁H₂₇N₅O₂.0.5C₄H₄O₄.0.3H₂O

[0521] Calculated(%): C, 62.09; H, 6.71; N, 15.74.

[0522] Found (%): C, 62.20; H, 6.72; N, 15.32.

EXAMPLE 53(R)-8-Benzyl-7,8-dihydro-4-(n-propyl)-2-(tetrahydropyran-4-yl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 53)

[0523] In a manner similar to that in Example 45, the title compound inthe free form (250 mg, 85%) was obtained from Compound B15 (230 mg,0.752 mmol) prepared in Reference Example 25 and (R)-phenylalaminol (170mg, 1.18 mmol, 1.6 equivalents), and it was converted into hydrochloridewith a 4 mol/L solution of hydrogen chloride in dioxane. The depositedsolid was washed with ethyl acetate to obtain the title compound (120mg, 37%).

[0524] Melting point: 226-227° C. (dioxane)

[0525]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.4 Hz), 1.70-1.83 (m,2H), 1.92-2.10 (m, 4H), 3.01 (dd, 1H, J=13.9, 7.9 Hz), 3.12 (m, 1H),3.23 (dd, 1H, J=13.9, 4.6 Hz), 3.53 (dt, 2H, J=11.6, 2.6 Hz), 4.03-4.12(m, 5H), 4.23 (dd, 1H, J=11.9, 9.9 Hz), 4.71 (m, 1H), 7.26-7.38 (m, 5H),11.4 (brs, 1H), 13.9 (brs, 1H).

[0526] IR (KBr) 2996, 1703, 1668, 744, 727 cm⁻¹

[0527] TOF-MS: m/z 394 (M⁺+1).

[0528] Elemental Analysis for C₂₂H₂₇N₅O₂—HCl

[0529] Calculated(%): C, 61.46; H, 6.56; N, 16.29.

[0530] Found (%): C, 61.34; H, 6.94; N, 16.16.

EXAMPLE 54(R)-8-Benzyl-7,8-dihydro-2-(trans-4-hydroxyhexyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 54)

[0531] In a manner similar to that in Example 45, a ketone compound (940mg, 98%) was obtained from Compound B16 (1.00 g, 3.25 mmol) prepared inReference Example 26 and (R)-phenylalaminol (740 mg, 4.89 mmol, 1.5equivalents). The ketone compound (300 mg, 0.741 mmol) was dissolved inmethanol (5 mL) and to the solution was added sodium borohydride (28 mg,0.741 mmol, 1.0 equivalent) with ice cooling. The ice bath was removed,and the reaction mixture was warmed to room temperature and stirred for20 hours. To the reaction mixture was added a small amount of acetone,the mixture was stirred, then the solvent was evaporated under reducedpressure, and the residue was partitioned with 2 mol/L aqueous sodiumhydroxide and chloroform. The resulting organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (chloroform:methanol=95:5) to obtainthe title compound in the free form (170 mg, 56%). The free compound (70mg, 0.172 mmol) was converted into hydrochloride with a 4 mol/L solutionof hydrogen chloride in dioxane to obtain the title compound (60 mg,80%).

[0532] Melting point: 115-116° C. (dioxane)

[0533]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.6 Hz), 1.40-1.83 (m,6H), 2.11-2.24 (m, 4H), 2.84 (ddd, 1H, J=8.6, 3.3, 3.3 Hz), 3.01 (dd,1H, J=13.9, 7.9 Hz), 3.23 (dd, 2H, J=13.9, 4.8 Hz), 3.72 (m, 1H),4.02-4.26 (m, 4H), 4.68 (m, 1H), 7.26-7.64 (m, 5H), 11.3 (brs, 1H), 13.8(brs, 1H).

[0534] IR (KBr) 2937, 1716, 1670, 752 cm⁻¹

[0535] TOF-MS: m/z 408 (M⁺+1).

[0536] Elemental Analysis for C₂₂H₂₉N₅O₂.HCl.2H₂O

[0537] Calculated(%): C, 57.55; H, 7.14; N, 14.59.

[0538] Found (%): C, 57.97; H, 7.34; N, 14.43.

EXAMPLE 55(R)-8-Benzyl-2-(1,3-dioxolane-2-spirocyclopentan-2′-yl)-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 55)

[0539] In a manner similar to that in Example 45, the title compound(720 mg, 39%) was obtained from Compound B17 (1.50 g, 4.29 mmol)prepared in Reference Example 27 and (R)-phenylalaminol (970 mg, 6.44mmol, 1.5 equivalents).

[0540]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (dt, 3H, J=7.4, 2.7 Hz), 1.72-2.09(m, 6H), 2.16-2.22 (m, 2H), 2.84 (dd, 1H, J=13.8, 7.5 Hz), 3.06 (m, 1H),3.37 (m, 1H), 3.65-4.05 (m, 8H), 4.43 (m, 1H), 7.20-7.31 (m, 5H).

[0541] IR (KBr) 1714, 1683, 1587, 746, 704 cm⁻¹

[0542] TOF-MS: m/z 436 (M⁺+1).

EXAMPLE 56(R)-8-Benzyl-2-benzyloxymethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 56)

[0543] In a manner similar to that in Example 45, the title compound inthe free form (109 mg) was obtained from Compound B18 (250 mg, 0.726mmol) prepared in Reference Example 28 and (R)-phenylalaminol (130 mg,0.860 mmol, 1.2 equivalents), and the title compound (62 mg, 18%) wasobtained as white crystals from the free compound and fumaric acid.

[0544] Melting point: 130-132° C. (ethyl acetate)

[0545]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.78 (q, 2H,J=7.3 Hz), 2.99 (dd, 1H, J=13.8, 7.6 Hz), 3.19 (dd, 1H, J=13.8, 5.0 Hz),4.01 (dd, 1H, J=11.6, 6.3 Hz), 4.06 (t, 2H, J=7.3 Hz), 4.19 (dd, 1H,J=11.9, 9.9 Hz), 4.65 (m, 1H), 4.70 (s, 4H), 6.91 (s, 2H), 7.22-7.46 (m,10H).

[0546] IR (KBr) 1716, 1675, 1654, 1578, 1454, 1365 cm⁻¹

[0547] EI-MS: m/z 430 (M⁺+1).

[0548] Elemental Analysis for C₂₅H₂₇N₅O₂.0.5C₄H₄O₄.0.3H₂O

[0549] Calculated(%): C, 65.79; H, 6.05; N, 14.21.

[0550] Found (%): C, 65.60; H, 6.02; N, 14.76.

EXAMPLE 57(R)-8-Benzyl-7,8-dihydro-2-(α-methoxybenzyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 57)

[0551] In a manner similar to that in Example 45, the title compound inthe free form (111 mg) was obtained from Compound B19 (176 mg, 0.511mmol) prepared in Reference Example 29 and (R)-phenylalaminol (120 mg,0.794 mmol, 1.5 equivalents), and the title compound (20 mg, 8%) wasobtained as white crystals from the free compound and fumaric acid.

[0552] Melting point: 160-162° C. (acetone/diethyl ether)

[0553]¹H-NMR (270 MHz, CDCl₃) δ 0.99 (t, 3H, J=7.2 Hz), 1.75 (q, 2H,J=7.2 Hz), 2.99 (dd, 1H, J=13.8, 7.9 Hz), 3.21 (dd, 1H, J=13.9, 5.6 Hz),3.49 (s, 3H), 4.07 (dd, 1H, J=11.6, 6.3 Hz), 4.14 (t, 2H, J=13.9 Hz),4.19 (dd, 1H, J=11.9, 9.9 Hz), 4.65 (m, 1H), 5.60 (s, 1H), 7.23 (s, 2H),7.28-7.40 (m, 8H), 7.60 (d, 2H, J=6.9 Hz).

[0554] IR (KBr) 1722, 1713, 1691, 1678, 1666, 1643, 1581, 1365 cm⁻¹

[0555] EI-MS: m/z 430 (M⁺).

[0556] Elemental Analysis for C₂₅H₂₇N₅O₂.0.5C₄H₄O₄.0.5H₂O

[0557] Calculated(%): C, 65.30; H, 6.09; N, 14.10.

[0558] Found (%): C, 65.38; H, 6.20; N, 14.19.

EXAMPLE 58(R)-8-Benzyl-7,8-dihydro-2-(2-methoxyethyl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 58)

[0559] In a manner similar to that in Example 45, the title compound inthe free form was obtained from Compound B20 (750 mg, 2.66 mmol)prepared in Reference Example 30 and (R)-phenylalaminol (610 mg, 4.03mmol, 1.5 equivalents), and it was converted into hydrochloride with a 4mol/L solution of hydrogen chloride in dioxane to obtain the titlecompound (820 mg, 76%).

[0560] Melting point: 150-151° C. (ethyl acetate/hexane)

[0561]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.6 Hz), 1.72-1.83 (m,2H), 3.00 (dd, 1H, J=13.9, 7.9 Hz), 3.14 (t, 2H, J=5.9 Hz), 3.24 (dd,1H, J=13.9, 4.6 Hz), 3.47 (s, 3H), 3.81 (t, 2H, J=5.9 Hz), 4.06 (t, 2H,J=7.3 Hz), 4.07 (dd, 1H, J=6.9, 5.9 Hz), 4.21 (dd, 1H, J=11.9, 9.9 Hz),4.71 (m, 1H), 7.25-7.36 (m, 5H), 11.8 (brs, 1H), 13.6 (brs, 1H).

[0562] IR (KBr) 2832, 1714, 1678, 744, 725 cm⁻¹

[0563] TOF-MS: m/z 368 (M⁺+1).

[0564] Elemental Analysis for C₂₀H₂₅N₅O₂.HCl

[0565] Calculated(%): C, 59.47; H, 6.49; N, 17.34.

[0566] Found (%): C, 59.43; H, 6.71; N, 17.09.

EXAMPLE 59(R)-8-Benzyl-2-(2-carboxylethyl)-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 59)

[0567] To Compound B21 (1.00 g, 3.78 mmol) obtained in Reference Example31 and (R)-phenylalaminol (860 mg, 5.67 mmol, 1.5 equivalents) was addedpyridine (10 mL) and the mixture was refluxed with heating for 9 hours.The solvent was evaporated under reduced pressure, then to the residuewas added water, and the mixture was partitioned with chloroform. Theresulting aqueous layer was concentrated to the solid state underreduced pressure, ethanol was added, and then the mixture was filtered.The resulting filtrate was concentrated to obtain a crude product. Theresulting product was desalted by using HP-22 to obtain(R)-8-(2-carboxyethyl)-6-[2-(1-hydroxy-3-phenylpropan-2-yl)amino]-3-(n-propyl)-7H-purin-2(3H)-one(1.05 g, 70%). The resulting carboxylic acid (1.00 g, 2.51 mmol) wasadded to a solution which was obtained by addition of thionyl chloride(732 μL, 10.0 mmol, 4.0 equivalents) to cooled methanol (50 mL), andthen the mixture was warmed to room temperature and stirred for 15hours. The reaction mixture was concentrated and partitioned withsaturated aqueous sodium hydrogen carbonate and ethyl acetate. Theresulting organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The resulting residuewas purified by silica gel column chromatography(chloroform:methanol=100:0 to 95:5) to obtain(R)-6-[2-(1-hydroxy-3-phenylpropan-2-yl)amino]-8-(2-methoxycarboxyethyl)-3-(n-propyl)-7H-purin-2(3H)-one(500 mg, 48%). To the resulting ester compound (250 mg, 0.61 mmol) wasadded thionyl chloride (1 mL) and the mixture was stirred at 60° C. for2 hours. Excess reagents were evaporated under reduced pressure, to thereaction mixture were added ethyl acetate and saturated aqueous sodiumhydrogen carbonate, and then the mixture was stirred. The reactionmixture was partitioned, and the resulting organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was purified by silica gel column chromatography(chloroform:methanol=99:1) to obtain(R)-8-benzyl-7,8-dihydro-2-(2-methoxycarboxyethyl)-4-(n-propyl)-1H-imidazo[2,1-i]-purin-5(4H)-one (260 mg, 99%). To the ester compound (180 mg, 0.46mmol) was added methanol (4 mL) and 2 mol/L aqueous sodium hydroxide (2mL) and the mixture was stirred at room temperature for 12 hours. Thereaction mixture was adjusted to pH 3 with 4 mol/L hydrochloric acid.The deposited solid was collected by filtration to obtain the titlecompound (140 mg, 80%).

[0568] Melting point: 274-276° C. (methanol/water)

[0569]¹H-NMR (270 MHz, DMSO-d₆) δ 0.86 (t, 3H, J=7.3 Hz), 1.60-1.68 (m,2H), 2.66 (t, 2H, J=7.3 Hz), 2.81-3.01 (m, 4H), 3.63 (dd, 1H, J=11.0,6.8 Hz), 3.80-3.96 (m, 3H), 4.51 (m, 1H), 7.18-7.30 (m, 5H).

[0570] IR (KBr) 1720, 1705, 1686 cm⁻¹

[0571] FAB-MS: m/z 382 (M⁺+1).

[0572] Elemental Analysis for C₂₀H₂₃N₅O₃.1.8H₂O

[0573] Calculated(%): C, 58.04; H, 6.48; N, 16.92.

[0574] Found (%): C, 58.24; H, 6.11; N, 17.14.

EXAMPLE 60(S)-8-(tert-Butyl)-7,8-dihydro-2-(1-methylsulfonylpiperidin-4-yl)-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 60)

[0575] In a manner similar to that in Example 45, the title compound (3mg, 14%) was obtained from Compound B22 (19 mg, 0.049 mmol) prepared inReference Example 32 and (S)-tert-butylalaminol (9 mg, 0.077 mmol, 1.5equivalents).

[0576]¹H-NMR (270 MHz, CDCl₃) δ 0.99 (t, 3H, J=7.6 Hz), 1.07 (s, 9H),1.74-1.85 (m, 2H), 1.95-2.17 (m, 2H), 2.18-2.27 (m, 2H), 2.83 (s, 3H),2.78-3.03 (m, 4H), 3.81-3.98 (m, 2H), 4.01-4.30 (m, 5H), 11.4 (brs, 1H).

[0577] TOF-MS: m/z 437 (M⁺+1).

EXAMPLE 61(R)-8-Benzyl-2-(1-tert-butoxycarbonylpiperidin-4-yl)-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 61)

[0578] In a manner similar to that in Example 45, the title compound inthe free form was obtained from Compound B23 (1.00 g, 2.46 mmol)prepared in Reference Example 33 and (R)-phenylalaminol (557 mg, 3.69mmol, 1.5 equivalents), and it was converted into hydrochloride with a 4mol/L solution of hydrogen chloride in dioxane to obtain the titlecompound (580 mg, 48%).

[0579] Melting point: 204-205° C. (diisopropyl ether/hexane)

[0580]¹H-NMR (270 MHz, CDCl₃) δ 0.95 (t, 3H, J=7.4 Hz), 1.47 (s, 9H),1.72-1.80 (m, 4H), 2.09-2.15 (m, 2H), 2.84-3.05 (m, 3H), 3.01 (dd, 1H,J=14.2, 7.6 Hz), 3.23 (dd, 1H, J=4.6, 14.2 Hz), 4.03-4.27 (m, 6H), 4.73(m, 1H), 7.22-7.37 (m, 5H), 11.3 (brs, 1H), 13.9 (brs, 1H).

[0581] IR (KBr) 2941, 1720, 1682, 744 cm⁻¹

[0582] EI-MS: m/z 492 (M⁺).

[0583] Elemental Analysis for C₂₇H₃₆N₆O₃.HCl.0.2H₂O

[0584] Calculated(%): C, 60.88; H, 7.08; N, 15.78.

[0585] Found (%): C, 60.85; H, 7.21; N, 15.47.

EXAMPLE 62(R)-2-[trans-4-(Aminomethyl)cyclohexyl]-8-benzyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 62)

[0586] In a manner similar to that in Example 45, an adduct was obtainedfrom Compound B24 prepared in Reference Example 34 and(R)-phenylalaminol, and the adduct (600 mg, 1.11 mmol) was dissolved inmethanol (5 mL). To the solution were added palladium hydroxide (600 mg,10% on carbon) and ammonium formate (400 mg, 10.8 mmol, 10.0equivalents), and the mixture was heated to 60° C. and stirred for 2hours. The reaction mixture was cooled to room temperature and filteredby using Celite, and the resulting filtrate was concentrated. To theresidue were added a small amount of water and sodium hydrogen carbonateand then the mixture was extracted with chloroform. The organic layerwas dried over anhydrous magnesium sulfate, concentrated and purified bysilica gel column chromatography (chloroform:methanol: ammonia=84:8:8)to obtain the title compound (150 mg, 32%).

[0587] Melting point: 70-71° C. (chloroform/methanol)

[0588]¹H-NMR (270 MHz, CDCl₃) δ 0.88-1.39 (m, 2H), 0.98 (t, 3H, J=7.4Hz), 1.54-2.17 (m, 9H), 2.54 (d, 2H, J=6.6 Hz), 2.66 (m, 1H), 2.82-2.88(m, 2H), 3.72 (dd, 1H, J=11.0, 6.8 Hz), 3.95-4.16 (m, 4H), 7.16-7.20 (m,5H).

[0589] IR (KBr) 2927, 1695, 1660, 746, 702 cm⁻¹

[0590] TOF-MS: m/z 421 (M⁺+1).

EXAMPLE 63(R)-2-[trans-4-(Acetamidomethyl)cyclohexyl]-8-benzyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 63)

[0591] Compound 62 (50 mg, 0.119 mmol) obtained in Example 62 wasdissolved in methylene chloride (500 μL), to the solution were addedacetic anhydride (11 μL, 0.119 mmol, 1.0 equivalent) and pyridine (10μL, 0.120 mmol, 1.0 equivalent), and the mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture was added saturatedaqueous sodium hydrogen carbonate and the mixture was extracted withethyl acetate. The resulting organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue waspurified by silica gel column chromatography (chloroform:methanol=100:0to 98:2) to obtain the title compound in the free form (50 mg). The freecompound was converted into hydrochloride with a 4 mol/L solution ofhydrogen chloride in dioxane and the product was recrystallized fromethanol to obtain the title compound (51 mg, 86%).

[0592]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.4 Hz), 1.01-1.09 (m,2H), 1.58-2.18 (m, 9H), 2.00 (s, 3H), 2.68 (m, 1H), 2.78-2.88 (m, 2H),3.10-3.17 (m, 2H), 3.75 (dd, 1H, J=10.3, 5.8 Hz), 3.94-4.07 (m, 4H),5.82 (brt, 1H), 7.13-7.17 (m, 5H), 7.60 (brs, 1H).

[0593] IR (KBr) 3244, 2925, 1716, 1668, 1637, 752 cm⁻¹

[0594] TOF-MS: m/z 463 (M⁺+1).

[0595] Elemental Analysis for C₂₆H₃₄N₆O₂.HCl.1.5H₂O

[0596] Calculated(%): C, 59.36; H, 7.28; N, 15.98.

[0597] Found (%): C, 59.42; H, 7.20; N, 15.63.

EXAMPLE 64(R)-8-Benzyl-2-ethylthiomethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 64)

[0598] In a manner similar to that in Example 45, the title compound inthe free form was obtained from Compound B25 (1.00 g, 3.36 mmol)prepared in Reference Example 35 and (R)-phenylalaminol (770 mg, 5.09mmol, 1.5 equivalents), and the title compound (139 mg, 10%) wasobtained as white crystals from the free compound and fumaric acid.

[0599] Melting point: 178-180° C. (methanol/acetone)

[0600]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.31 (t, 3H,J=7.6 Hz), 1.78 (q, 2H, J=7.3 Hz), 2.66 (q, 2H, J=7.6 Hz), 3.00 (dd, 1H,J=13.8, 7.9 Hz), 3.22 (dd, 1H, J=13.8, 4.9 Hz), 3.87 (s, 2H), 4.04 (dd,1H, J=11.6, 6.6 Hz), 4.07 (t, 2H, J=7.3 Hz), 4.19 (dd, 1H, J=11.6, 9.6Hz), 4.70 (m, 1H), 6.88 (s, 2H), 7.24-7.36 (m, 5H).

[0601] IR (KBr) 1713, 1680, 1655, 1574, 1362, 1273 cm⁻¹

[0602] EI-MS: m/z 384 (M⁺+1).

[0603] Elemental Analysis for C₂₀H₂₅N₅OS.0.5C₄H₄O₄.0.1H₂O

[0604] Calculated(%): C, 59.60; H, 6.18; N, 15.80.

[0605] Found (%): C, 59.44; H, 6.08; N, 16.05.

EXAMPLE 65(R)-8-Benzyl-2-ethylsulfonylmethyl-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1i]purin-5(4H)-one0.5 fumarate (Compound 65)

[0606] Compound 64 (593 mg, 1.55 mmol) obtained in Example 64 wasdissolved in methanol (20 mL) and water (5 mL), to the solution wasadded OXONE® (3.80 g, 6.18 mmol, 4.0 equivalents), and the mixture wasstirred at room temperature for 4 hours. To the reaction mixture wasadded saturated aqueous sodium hydrogen carbonate and the mixture wasextracted with ethyl acetate. The resulting organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography(chloroform:methanol=100:0 to 98:2) to obtain the title compound in thefree form. The title compound (311 mg, 49%) was obtained as whitecrystals from the free compound and fumaric acid.

[0607] Melting point: 180-182° C. (ethyl acetate)

[0608]¹H-NMR (270 MHz, CDCl₃) δ 0.96 (t, 3H, J=7.3 Hz), 1.46 (t, 3H,J=7.3 Hz), 1.75 (q, 2H, J=7.3 Hz), 3.03 (dd, 1H, J=13.9, 7.3 Hz), 3.16(dd, 1H, J=13.9, 5.6 Hz), 3.24 (q, 2H, J=7.6 Hz), 4.06 (dd, 1H, J=11.9,4.6 Hz), 4.08 (t, 2H, J=7.3 Hz), 4.26 (dd, 1H, J=11.9, 9.6 Hz), 4.46 (s,2H), 4.70 (m, 1H), 6.84 (s, 2H), 7.23-7.37 (m, 5H).

[0609] IR (KBr) 1720, 1687, 1657, 1560, 1315, 1119 cm⁻¹

[0610] EI-MS: m/z 416 (M⁺+1).

[0611] Elemental Analysis for C₂₀H₂₅N₅O₃S 0.5C₄H₄₀₄-0.4H₂O

[0612] Calculated(%): C, 54.74; H, 5.77; N, 14.33.

[0613] Found (%): C, 54.76; H, 5.85; N, 14.51.

EXAMPLE 66(R)-1,8-Dibenzyl-5-chloro-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purine(Compound 66)

[0614] To Compound C2 (1.87 g, 4.05 mmol) obtained in Reference Example37 was added thionyl chloride (15.0 mL, 207 mmol, 51 equivalents) andthe mixture was stirred with heating at 60° C. for 1 hour. The reactionsolution was concentrated under reduced pressure, the solvent wasazeotroped with toluene, to the residue were carefully added chloroformand saturated sodium hydrogen carbonate, and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was extracted withchloroform, then the organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, and the solventwas evaporated. The residue was purified by silica gel columnchromatography (chloroform:methanol=90:10) to obtain the title compound(1.87 g, 99%).

[0615] Melting point: 124-125° C. (ethyl acetate)

[0616]¹H-NMR (270 MHz, CDCl₃) δ 1.51-1.63 (m, 2H), 1.67-1.98 (m, 6H),2.73 (dd, 1H, J=13.5, 8.3 Hz), 3.01 (quin, 1H, J=8.0 Hz), 3.08 (dd, 1H,J=13.5, 5.1 Hz), 3.83 (dd, 1H, J=11.2, 6.9 Hz), 4.04 (dd, 1H, J=11.2,10.2 Hz), 4.57 (m, 1H), 5.53 (d, 1H, J=15.9 Hz), 5.62 (d, 1H, J=15.9Hz), 7.10-7.38 (m, 10H).

[0617] IR (KBr) 1684, 1498, 1454, 1377, 1333 cm⁻¹

[0618] EI-MS: m/z 444 (M⁺+1).

EXAMPLE 67(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(n-propylamino)-1H-imidazo[2,1-i]purine(Compound 67)

[0619] In a manner similar to that in Example 66,(R)-8-benzyl-5-chloro-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1i]purine(Compound 67a) was obtained from Compound C10 prepared in ReferenceExample 44. To Compound 67a (200 mg, 0.244 mmol) was added n-propylamine(2 mL) and the mixture was stirred under reflux with heating for 3 hour.The reaction mixture was concentrated, and the residue was purified bysilica gel column chromatography (chloroform:methanol=95:5, chloroform:a 7 mol/L ammonia/methanol solution =95:5) to obtain the title compound(183 mg, 99%) as an ocher solid.

[0620] Melting point: 108-110° C. (chloroform/methanol)

[0621]¹H-NMR (270 MHz, CDCl₃) δ 0.89 (t, 3H, J=7.6 Hz), 1.58-1.95 (m,8H), 2.07-2.15 (m, 2H), 2.91 (dd, 1H, J=14.0, 6.2 Hz), 2.97 (dd, 1H,J=14.0, 7.6 Hz), 3.22 (q, 1H, J=8.4 Hz), 3.40 (t, 2H, J=7.3 Hz), 4.08(m, 1H), 4.29-4.41 (m, 2H, 7.11-7.27 (m, 5H).

[0622] IR (CHCl₃) 3018, 1693, 1574, 1556, 1367 cm⁻¹

[0623] EI-MS: m/z 377 (M⁺+1).

EXAMPLE 68(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(2-piperidinoethylamino)-1H-imidazo[2,1-i]purine(Compound 68)

[0624] Compound 67a (100 mg, 0.240 mmol) obtained in Example 67 wasdissolved in tetrahydrofuran (2 mL), and to the solution were added2-piperidinoethylamine (61 μL, 0.480 mmol, 2.0 equivalents) andN,N-diisopropylethylamine (344 μL, 0.960 mmol, 4.0 equivalents) and themixture was stirred at 80° C. for 2 hours. The reaction mixture wasconcentrated, and then the residue was purified by silica gel columnchromatography (chloroform:methanol=90:10, chloroform: a 7 mol/Lammonia/methanol solution=90:10). To the product was added diisopropylether, and the deposited crystals were collected by filtration and driedto obtain the title compound (110 mg, 94%) as white crystals.

[0625] Melting point: 154-156° C. (diisopropyl ether)

[0626]¹H-NMR (270 MHz, CDCl₃) δ 1.48-2.06 (m, 14H), 2.38-2.46 (m, 4H),2.56 (t, 2H, J=5.9 Hz), 2.84 (dd, 1H, J=13.8, 8.1 Hz), 3.14-3.24 (m,2H), 3.49 (t, 2H, J=5.9 Hz), 3.71 (dd, 1H, J=10.0, 6.8 Hz), 3.92 (t, 1H,J=10.0 Hz), 4.53 (m, 1H), 7.20-7.26 (m, 5H).

[0627] IR (CHCl₃) 1682, 1568, 1556, 1531 cm⁻¹

[0628] EI-MS: m/z 446 (M⁺+1)

EXAMPLE 69(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(1-pyrrolidinyl)-1H-imidazo[2,1-i]purine(Compound 69)

[0629] In a manner similar to that in Example 67, the title compound (50mg, 36%) was obtained as an ocher solid from Compound 67a (296 mg, 0.361mmol) and pyrrolidine (2 mL).

[0630] Melting point: 202-204° C. (chloroform/methanol)

[0631]¹H-NMR (270 MHz, CDCl₃) δ 1.69-2.00 (m, 10H), 2.12-2.19 (m, 2H),3.00 (dd, 1H, J=13.8, 7.8 Hz),2.95-3.31 (m, 2H),3.54-3.62 (m, 4H), 4.27(dd, 1H, J=10.5, 6.2 Hz), 4.48 (t, 1H, J=10.5 Hz), 4.67 (m, 1H),7.24-7.35 (m, 5H).

[0632] IR (CHCl₃) 1713, 1681, 1556, 1520 cm⁻¹

[0633] EI-MS: m/z 389 (M⁺+1)

Example 70(R)-8-Benzyl-2-(tert-butyl)-5-ethoxy-7,8-dihydro-1H-imidazo[2,1-i]purine(Compound 70)

[0634] In a manner similar to that in Example 66, a cyclized compoundwas obtained from Compound C8 prepared in Reference Example 43, to asolution of the cyclized compound (4.88 g, 14.3 mmol) in ethanol (30 mL)was added a 21% solution of sodium ethoxide (30 mL, 93.0 mmol, 6.5equivalents) in ethanol, and then the mixture was stirred with heatingat 70° C. for 3 hours. The reaction solution was concentrated, and thedeposited crystals were collected by filtration and recrystallized fromethyl acetate to obtain the title compound (2.67 g, 54%) as whitecrystals.

[0635] Melting point: 220-222° C. (ethyl acetate)

[0636]¹H-NMR (270 MHz, CDCl₃) δ 1.37 (t, 3H, J=7.3 Hz), 1.41 (s, 9H),2.80 (dd, 1H, J=13.9, 7.9 Hz), 3.11 (dd, 1H, J=13.9, 6.3 Hz), 3.71 (dd,1H, J=11.3, 7.3 Hz), 3.99 (dd, 1H, J=11.3, 9.9 Hz), 4.48 (q, 2H, J=7.3Hz), 4.55 (m, 1H), 7.24-7.35 (m, 5H).

[0637] IR (KBr) 1678, 1668, 1655, 1558, 1539, 1431, 1350 cm⁻¹

[0638] EI-MS: m/z 351 (M⁺).

[0639] Elemental Analysis for C₂₀H₂₅N₅O.0.2H₂O

[0640] Calculated(%): C, 67.66; H, 7.21; N, 19.72.

[0641] Found (%): C, 67.70; H, 7.37; N, 19.62.

EXAMPLE 71(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(3-methylthiopropyloxy)-1H-imidazo[2,1-i]purine(Compound 71)

[0642] To a solution of Compound 67a (240 mg, 0.585 mmol) obtained inExample 67 in tetrahydrofuran (2 mL) were added 2-methylthiopropanol (1mL) and sodium hydride (containing 34% mineral oil, 88 mg, 2.34 mmol),then Compound 67a (240 mg, 0.585 mmol) was further added to the mixture,and stirring was continued at 100° C. for 4 hours. To the reactionmixture was added ethyl acetate, and the mixture was washed twice withwater and dried over magnesium sulfate. The reaction mixture wasconcentrated, and the residue was purified by silica gel columnchromatography (chloroform:methanol=99:1) to obtain the title compound(100 mg, 40%) as an ocher foamy solid.

[0643]¹H-NMR (270 MHz, CDCl₃) δ 1.68-2.18 (m, 10H), 2.11 (s, 3H), 2.60(t, 2H, J=6.8 Hz), 2.97 (dd, 1H, J=13.8, 7.8 Hz), 3.22 (dd, 1H, J=13.8,4.9 Hz), 3.31 (m, 1H), 4.05 (dd, 1H, J=11.9, 6.8 Hz), 4.25 (t, 1H,J=11.3 Hz), 4.61 (t, 2H, J=6.5 Hz), 4.64 (m, 1H), 7.23-7.34 (m, 5H)

[0644] IR (CHCl₃) 1702, 1579, 1538, 1417, 1371 cm⁻¹

[0645] EI-MS: m/z 424 (M⁺+1)

EXAMPLE 72(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(3-methylsulfonylpropyloxy)-1H-imidazo[2,1-i]purine(Compound 72)

[0646] In a manner similar to that in Example 65, the title compound (25mg, 29%) was obtained as an ocher foamy solid from Compound 71 (80 mg,0.190 mmol) obtained in Example 71.

[0647]¹H-NMR (270 MHz, CDCl₃) δ 1.67-2.06 (m, 8H), 2.30-2.38 (m, 2H),2.83 (dd, 1H, J=7.0, 14.0 Hz), 2.94 (s, 3H), 3.06 (m, 1H), 3.12-3.23 (m,3H), 3.80 (dd, 1H, J=7.0, 11.3 Hz), 4.03 (t, 1H, J=10.8 Hz), 4.40 (m,1H), 4.61 (t, 2H, J=6.5 Hz), 7.20-7.37 (m, 5H)

[0648] IR (CHCl₃) 1693, 1681, 1539, 1311, 1136 cm⁻¹

[0649] EI-MS: m/z 456 (M⁺+1)

EXAMPLE 73(R)-8-Benzyl-2-(tert-butyl)-7,8-dihydro-5-methylthio-1H-imidazo[2,1i]purine(Compound 73)

[0650] In a manner similar to that in Example 66, the title compound(1.12 g, 36%) was obtained as white crystals from Compound C9 (3.30 g,8.90 mmol) prepared in Reference Example 43.

[0651] Melting point: 171-174° C. (acetone/diethyl ether)

[0652]¹H-NMR (270 MHz, CDCl₃) δ 1.42 (s, 9H), 2.63 (s, 3H), 2.82 (dd,1H, J=13.8, 7.9 Hz), 3.11 (dd, 1H, J=13.8, 5.8 Hz), 3.73 (dd, 1H,J=10.2, 6.9 Hz), 4.00 (t, 1H, J=10.2 Hz), 4.59 (dq, 2H, J=9.9, 6.9 Hz),7.23-7.36 (m, 5H).

[0653] IR (KBr) 1670, 1518, 1501, 1408, 1344 cm⁻¹

[0654] EI-MS: m/z 354 (M⁺+1).

[0655] Elemental Analysis for C₁₉H₂₃N₅S.0.2H₂O

[0656] Calculated(%): C, 63.91; H, 6.60; N, 19.61.

[0657] Found (%): C, 63.70; H, 6.54; N, 19.89.

EXAMPLE 74(R)-8-Benzyl-2-cyclopentyl-5-ethyl-7,8-dihydro-1H-imidazo[2,1-i]purine(Compound 74)

[0658] Compound 67a (82 mg, 0.20 mmol) obtained in Example 67 wasdissolved in tetrahydrofuran (1 mL), to the solution was added a 1 mol/Lsolution (2 mL) of ethyl magnesium bromide in tetrahydrofuran, and themixture was stirred at 60° C. for 1 hour. To the reaction mixture wasadded water and the mixture was stirred. Ethyl acetate was added to themixture and the organic layer was washed with water and dried overmagnesium sulfate. The organic layer was concentrated and to the residuewere added dichloromethane and diisopropyl ether. The deposited crystalswere collected by filtration to obtain the title compound (40 mg, 58%)as a white solid.

[0659] Melting point: 187-189° C. (dichloromethane/diisopropyl ether)

[0660]¹H-NMR (270 MHz, CDCl₃) δ 1.37 (t, 3H, J=7.6 Hz), 1.64-2.10 (m,8H), 2.62 (q, 2H, J=7.6 Hz), 2.77 (dd, 1H, J=13.8, 5.9 Hz), 2.95 (dd,1H, J=13.8, 6.8 Hz), 3.23 (q, 1H, J=8.4 Hz), 3.79 (m, 1H), 4.02-4.09 (m,2H), 7.10-7.13 (m, 5H).

[0661] IR (CHCl₃) 1680, 1539, 1417, 1338 cm⁻¹

[0662] EI-MS: m/z 348 (M⁺+1)

EXAMPLE 75(R)-8-Benzyl-5-cyano-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purine(Compound 75)

[0663] Compound 67a (217 mg, 0.529 mmol) obtained in Example 67 wasdissolved in N,N-dimethylformamide (4 mL), to the solution were addedcesium carbonate (245 mg, 0.750 mmol, 1.5 equivalents) and potassiumcyanide (39 mg, 0.600 mmol, 1.2 equivalents), and the mixture wasstirred at 100° C. for 4 hours. To the reaction mixture was added water,and the deposited crystals were collected by filtration to obtain thetitle compound (125 mg, 73%) as a yellow solid.

[0664] Melting point: 140-142° C. (water)

[0665]¹H-NMR (270 MHz, CDCl₃) δ 1.65-2.07 (m, 8H), 2.79-2.94 (m, 2H),3.19 (q, 1H, J=8.4 Hz), 3.94-4.04 (m, 2H), 4.27 (m, 1H), 7.11-7.19 (m,5H).

[0666] IR (CHCl₃) 2246, 1664, 1454, 1421, 1388 cm⁻¹

[0667] EI-MS: m/z 345 (M⁺+1)

EXAMPLE 76(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-5-(1H-tetrazol-5-yl)-1H-imidazo[2,1-i]purine(Compound 76)

[0668] Compound 75 (69 mg, 0.200 mmol) obtained in Example 75 wasdissolved in 1-methyl-2-pyrrolidinone (1 mL), to the solution were addedsodium azide (52 mg, 0.800 mmol, 4.0 equivalents) and ammonium chloride(42 mg, 0.800 mmol, 4.0 equivalents), and the mixture was stirred at120° C. for 2 hours. To the reaction mixture was added water, and thedeposited crystals were collected by filtration to obtain the titlecompound (64 mg, 83%) as a white solid.

[0669] Melting point: 268-270° C. (water)

[0670]¹H-NMR (270 MHz, DMSO-d₆) δ 1.69-2.08 (m, 8H), 3.07 (dd, 1H,J=13.8, 4.9 Hz), 3.12 (dd, 1H, J=13.8, 7.3 Hz), 3.28 (m, 1H), 4.76 (m,1H), 4.88 (m, 1H), 5.03 (m, 1H), 7.22-7.35 (m, 5H), 10.9 (brs, 1H), 13.8(brs, 1H)

[0671] IR (CHCl₃) 1703, 1556, 1410, 1385 cm⁻¹

[0672] EI-MS: m/z 388 (M⁺+1)

EXAMPLE 77(R)-8-Benzyl-4-carboxymethyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 77)

[0673] Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 wasdissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/Laqueous sodium hydroxide (15 mL), and the mixture was stirred withheating at 70° C. for 3 hours. The reaction solution was concentratedunder reduced pressure, and then the residue was neutralized by additionof concentrated hydrochloric acid. The deposited crystals were collectedby filtration, washed with water and dried to obtain(R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) wasdissolved in N,N-dimethylformamide (5 mL), to the solution were addedpotassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoaceticacid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixturewas stirred at room temperature for 12 hours. The reaction solution wasconcentrated under reduced pressure, water was added to the concentrate,the mixture was extracted with chloroform, and the extract was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=90:10) to obtain(R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol),(R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1i]purin-5(4H)-one(Compound 77c, 220 mg, 29%) was obtained in a manner similar to themethod by which Compound 40 was obtained from Adduct 40a in Example 40.Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent oftetrahydrofuran (1 mL) and water (1 mL), to the solution was addedlithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture wasstirred at room temperature for 2.5 hours. The reaction mixture wasadjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solidwas washed with ethanol and collected by filtration to obtain the titlecompound (180 mg, 93%).

[0674] Melting point: 280° C. (decomposition)

[0675]¹H-NMR (270 MHz, DMSO-d₆) δ 1.59-1.96 (m, 8H), 2.85 (m, 1H), 2.97(m, 1H), 3.05 (m, 1H), 3.54 (m, 1H), 3.88 (t, 1H, J=9.9 Hz), 4.48 (s,2H), 4.45-4.54 (m, 1H), 7.20-7.31 (m, 5H).

[0676] IR (KBr) 1716, 1704, 1687 cm⁻¹

[0677] FAB-MS: m/z 394 (M⁺+1).

[0678] Elemental Analysis for C₂₁H₂₃N₅O₃.2H₂O

[0679] Calculated(%): C, 58.73; H, 6.34; N, 16.31.

[0680] Found (%): C, 58.90; H, 6.25; N, 16.33.

EXAMPLE 78((R)-8-Benzyl-2-cyclopentyl-4,5,7,8-tetrahydro-5-oxo-1H-imidazo[2,1-i]purine-4-yl)-n-propylacetamide(Compound 78)

[0681] Compound 77(50 mg, 0.127 mmol) obtained in Example 77 wasdissolved in water (1 mL) and 1,4-dioxane (1 mL), to the solution wereadded n-propylamine (14 μL, 0.176 mmol, 1.4 equivalents) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg,0.127 mmol, 1.0 equivalent), and the mixture was stirred at roomtemperature for 4 days. The reaction solution was extracted withchloroform, and the extract was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=98:2 to 90:10) to obtain the title compound (25 mg,45%).

[0682]¹H-NMR (270 MHz, CDCl₃) δ 0.90 (t, 3H, J=7.3 Hz), 1.49-1.59 (m,2H), 1.63-2.02 (m, 8H), 2.78 (d, 2H, J=5.6 Hz), 3.06 (m, 1H), 3.24 (t,2H, J=7.3 Hz), 3.67 (dd, 1H, J=10.2, 7.0 Hz), 3.84 (m, 1H), 3.94 (t, 1H,J=10.2 Hz), 4.71 (s, 2H), 6.38 (s, 1H), 7.08-7.21 (m, 5H).

[0683] IR (KBr) 3301, 2913, 1697, 1685, 1662, 1654 cm⁻¹

[0684] TOF-MS: m/z 435 (M⁺+1)

EXAMPLE 79(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-[3-(2-oxazolidinon-3-yl)propyl]-1H-imidazo[2,1-i]purin-5(4H)-one0.5 fumarate (Compound 79)

[0685] Compound 77a (130 mg, 0.332 mmol) obtained in Example 77 wasdissolved in N,N-dimethylformamide (1 mL), to the solution was addedpotassium carbonate (138 mg, 1.00 mmol, 3.0 equivalents), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added a solution of 3-(3-chloropropyl)-2-oxazolidinone (122mg, 0.750 mmol, 2.3 equivalents), which was prepared by the methoddescribed in EP747356A (International Patent Publication in Japanese No.8-337570), in N,N-dimethylformamide (1 mL) and then the mixture wasstirred at room temperature for 12 hours. The solvent was evaporated,and then to the residue was added water and the mixture was extractedwith chloroform. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and purified by silica gel columnchromatography (chloroform:methanol=100:5) to obtain an adduct (170 mg,99%). Then, debenzylation was carried out in a manner similar to themethod by which Compound 40 was obtained from Adduct 40a in Example 40.To the resulting residue were added fumaric acid and methanol, and themixture was concentrated. To the residue were added acetone and diethylether for crystallization to obtain the title compound (30 mg, 39%) aswhite crystals.

[0686] Melting point: 210-212° C. (acetone/diethyl ether)

[0687]¹H-NMR (270 MHz, CDCl₃) δ 1.70-1.90 (m, 2H), 1.90-2.00 (m, 4H),2.04 (m, 2H), 2.10-2.25 (m, 2H), 2.97 (dd, 1H, J=13.8, 8.6 Hz), 3.27 (m,2H), 3.36 (t, 2H, J=6.7 Hz), 3.62 (dd, 2H, J=8.9, 7.1 Hz), 4.03 (dd, 1H,J=11.9, 6.7 Hz), 4.14 (m, 3H), 4.35 (dd, 2H, J=8.9, 7.1 Hz), 4.71 (m,1H), 7.20-7.35 (m, 5H), 8.52 (s, 2H).

[0688] IR (KBr) 1738, 1722, 1672, 1581, 1371 cm⁻¹

[0689] Elemental Analysis for C₂₅H₃₀N₆O₃.0.5C₄H₄O₄.0.5H₂O

[0690] Calculated(%): C, 61.23; H, 6.28; N, 15.87.

[0691] Found (%): C, 61.38; H, 6.35; N, 15.86.

EXAMPLE 80(R)-2-Cyclopentyl-8-(4-fluorobenzyl)-7,8-dihydro-4-(2-hydroxyethyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 80)

[0692] To Compound C3 obtained in Reference Example 38 was added thionylchloride, and a cyclized compound was obtained in a manner similar tothat in Example 66. From the resulting cyclized compound, a hydrolyzedcompound was obtained in a manner similar to the method by whichCompound 77a was obtained from the Compound 66 in Example 77. From theresulting hydrolyzed compound (590 mg, 1.33 mmol) and2-(2-bromoethoxy)tetrahydro-2H-pyran (400 μL, 2.65 mmol, 2.0equivalents), an adduct (0.56 g, 74%) was obtained in a manner similarto that in Example 79, and the residue was dissolved in methanol (10mL). To the mixture was added p-toluenesulfonic acid monohydrate and themixture was stirred with heating at 60° C. for 2 hours. The reactionsolution was concentrated and directly purified by silica gel columnchromatography (chloroform:methanol=98:2 to 97:3). Then, the titlecompound in the free form was obtained in a manner similar to the methodby which Compound 40 was obtained from Adduct 40a in Example 40. To theresulting free compound were added a 4 mol/L solution of hydrogenchloride in dioxane (2 mL) and methanol (2 mL), the mixture wasconcentrated, and the residue was crystallized from acetone and diethylether to obtain the title compound (210 mg, 49%) as a white solid.

[0693] Melting point: 165-167° C. (acetone/diethyl ether)

[0694]¹H-NMR (270 MHz, CDCl₃) δ 1.60-1.72 (m, 2H), 1.74-1.91 (m, 4H),1.92-2.10 (m, 2H), 2.83 (d, 2H, J=6.2 Hz), 3.07 (quin, 1H, J=7.6 Hz),3.73 (dd, 2H, J=10.2, 5.6 Hz), 3.91-4.09 (m, 3H), 4.32 (t, 2H, J=4.3Hz), 6.84-6.90 (m, 2H), 7.07-7.18 (m, 2H).

[0695] IR (KBr) 1716, 1701, 1695, 1684, 1589, 1508, 1219 cm⁻¹

[0696] EI-MS: m/z 398 (M⁺+1).

[0697] Elemental Analysis for C₂₁H₂₄FN₅O₂.1.0HCl.0.5H₂O

[0698] Calculated(%): C, 56.95; H, 5.92; N, 15.81.

[0699] Found (%): C, 56.99; H, 6.01; N, 15.49.

EXAMPLE 81(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-(2-hydroxy-2-methylpropyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 81)

[0700] Compound 77c (670 mg, 1.65 mmol) obtained in Example 77 wasdissolved in tetrahydrofuran (7 mL), to the solution was added methylmagnesium bromide (2.75 mL, a 3.0 mol/L solution in diethyl ether, 5.0equivalents) under ice cooling, and the mixture was stirred at the sametemperature for 2 hours. To the reaction mixture was added saturatedaqueous ammonium chloride, and the mixture was warmed to roomtemperature and stirred for 10 minutes. The reaction mixture wasextracted with chloroform, and the resulting organic layer was washedwith saturated aqueous sodium hydrogen carbonate and saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography(chloroform:methanol=99:1). The product was converted into hydrochloridewith a 4 mol/L solution of hydrogen chloride in dioxane, and then, afterthe solvent was evaporated, the product was recrystallized from ethylacetate to obtain the title compound (460 mg, 68%).

[0701]¹H-NMR (270 MHz, CDCl₃) δ 1.23 (s, 3H), 1.25 (s, 3H), 1.67-1.93(m, 8H), 2.96-3.09 (m, 1H), 3.26 (d, 2H, J=6.2 Hz), 3.93-4.34 (m, 4H),4.72 (m, 1H), 7.19-7.39 (m, 5H).

[0702] IR (KBr) 2968, 1685, 1662, 1654, 1546, 1496 cm⁻¹

[0703] TOF-MS: m/z 408 (M⁺+1)

[0704] Elemental Analysis for C₂₃H₂₉N₅O₂.HCl

[0705] Calculated(%): C, 61.97; H, 6.83; N, 15.71.

[0706] Found (%): C, 61.95; H, 6.90; N, 15-0.45.

EXAMPLE 82(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-(3-hydroxypropyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 82)

[0707] An adduct (190 mg, 0.340 mmol) obtained from Compound 77aprepared in Example 0.77 and 2-(3-bromopropoxy)tetrahydro-2H-pyran wasdissolved in methanol (5 mL), to the solution were added palladiumhydroxide (20 mg, 10% on carbon) and ammonium formate (230 mg, 3.42mmol), and the mixture was stirred at 50° C. for 3 hours. The reactionmixture was filtered by using a filtration aid, and the resultingfiltrate was concentrated. To the residue were added water andchloroform for extraction, and the resulting organic layer was driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresulting residue was purified by preparative silica gel thin layerchromatography (chloroform:methanol=95:5) to obtain a debenzylatedcompound (0.11 g). The product was dissolved in tetrahydrofuran (1 mL),to the solution was added 1 mol/L hydrochloric acid (1 mL), and themixture was stirred at room temperature for 4 hours. The reactionmixture was adjusted to pH 7 with saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. Theresulting organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated. The resulting oil was purified bypreparative silica gel thin layer chromatography(chloroform:methanol=95:5) to obtain the title compound in the freeform. The resulting oil was dissolved in dioxane (1 mL) and convertedinto hydrochloride by addition of a 4 mol/L solution of hydrochloricacid in dioxane. The solvent was evaporated under reduced pressure, andthe residue was crystallized from ethyl acetate and hexane to obtain thetitle compound (40 mg, 27%).

[0708] Melting point: 187-188° C. (ethyl acetate/hexane)

[0709]¹H-NMR (270 MHz, CDCl₃) δ 1.64-2.07 (m, 10H), 2.70-2.82 (m, 2H),3.08 (m, 1H), 3.53 (brt, 2H, J=5.3 Hz), 3.64-3.71 (m, 2H), 3.95 (m, 1H),4.26 (t, 2H, J=5.6 Hz), 7.07-7.17 (m, 5H).

[0710] IR (KBr) 2787, 1718, 1683, 744, 727, 696 cm⁻¹

[0711] FAB-MS: m/z 384 (M⁺+1).

[0712] Elemental Analysis for C₂₂H₂₆N₅O₂.HCl.0.5H₂O

[0713] Calculated(%): C, 60.34; H, 6.44; N, 15.99.

[0714] Found (%): C, 60.10; H, 6.68; N, 15.54.

EXAMPLE 83(R)-8-Benzyl-2-(tert-butyl)-7,8-dihydro-4-(3-hydroxypropyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 83)

[0715] A cyclized compound was obtained by using Compound C6 prepared inReference Example 41 in a manner similar to that in Example 66, fromwhich(R)-1,8-dibenzyl-2-(tert-butyl)-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one(Compound 83a) was obtained in a manner similar to the method by whichCompound 77a was obtained from the Compound 66 in Example 77. Then thetitle compound was obtained in a manner similar to that in Example 82.

[0716]¹H-NMR (270 MHz, CDCl₃) δ 1.36 (s,9H), 1.90 (m,2H), 2.89 (dd, 1H,J=13.8, 6.8 Hz), 2.99 (dd, 1H, J=13.8, 7.3 Hz), 3.47 (t, 2H, J=5.5 Hz),3.82 (dd, 1H, J=11.3, 6.6 Hz), 4.10 (dd, 1H, J=11.3, 9.7 Hz), 4.22 (t,2H, J=5.7 Hz), 4.47 (m, 1H), 4.70 (brs, 2H), 7.16-7.34 (m, 5H).

[0717] EI-MS: m/z 382 (M⁺+1).

EXAMPLE 841-((R)-8-Benzyl-2-cyclopentyl-4,5,7,8-tetrahydro-5-oxo-1H-imidazo[2,1-i]purin-4-yl)butan-3-oneethylene acetal (Compound 84)

[0718] In a manner similar to that in Example 79, the title compound(400 mg, 76%) was obtained from Compounds 77a (500 mg) prepared inExample 77 and 2-(2-bromoethyl)-2-methyl-1,3-dioxolane.

[0719] Melting point: 200-201° C. (ethyl acetate)

[0720]¹H-NMR (270 MHz, CDCl₃) δ 1.38 (s, 3H), 1.72-1.88 (m, 6H),2.10-2.18 (m, 4H), 2.99 (dd, 1H, J=13.8, 7.6 Hz), 3.24 (dd, 1H, J=13.8,4.5 Hz), 3.28 (m, 1H), 3.89-3.95 (m, 4H), 4.06 (dd, 1H, J=11.9, 6.8 Hz),4.16-4.25 (m, 3H), 4.71 (m, 1H), 7.23-7.36 (m, 5H), 11.4 (brs, 1H).

[0721] IR (KBr) 1718, 1683, 1591 cm⁻¹

[0722] TOF-MS: m/z 450 (M⁺+1).

[0723] Elemental Analysis for C₂₅H₃₁N₅O₃.0.5H₂O

[0724] Calculated(%): C, 65.48; H, 7.03; N, 15.27.

[0725] Found (%): C, 65.28; H, 7.06; N, 15.10.

EXAMPLE 85(R)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-(3-hydroxy-3-methylbutyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 85)

[0726] Compound 84 (1.20 g, 2.67 mmol) obtained in Example 84 wasdissolved in acetone (50 mL), to the solution was addedp-toluenesulfonic acid hydrate (60 mg, 0.320 mmol, 0.12 equivalent), andthe mixture was stirred with heating at 80° C. for 3 hours. The solventwas evaporated under reduced pressure, to the residue were addedtetrahydrofuran (32 mL) and 1 mol/L hydrochloric acid (32 mL), and themixture was stirred at room temperature for 1 hour. The solvent wasevaporated, the residue was adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate, and the mixture was extracted withchloroform. The resulting organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the resulting residuewas purified by silica gel column chromatography (chloroform) to obtaina ketone compound (400 mg, 37%). The ketone compound (400 mg, 0.990mmol) was dissolved in tetrahydrofuran (14 mL), to the solution wasadded methyl magnesium bromide (2.43 mL, a 1.0 mol/L solution intetrahydrofuran) under ice cooling, and the mixture was stirred at thesame temperature for 2 hours. To the reaction mixture was addedsaturated aqueous ammonium chloride, and the mixture was warmed to roomtemperature and stirred for 10 minutes. The reaction mixture wasextracted with chloroform, and the resulting organic layer was washedwith saturated aqueous sodium hydrogen carbonate and saturated aqueoussodium chloride and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was purified by silica gel columnchromatography (chloroform:methanol=95:5) to obtain the title compoundin the free form. The free compound was converted into hydrochloridewith a 4 mol/L solution of hydrogen chloride in dioxane, and, after thesolvent was evaporated, recrystallization was carried out from ethylacetate to obtain the title compound (230 mg, 51%).

[0727] Melting point: 206-207° C. (ethyl acetate)

[0728]¹H-NMR (270 MHz, CDCl₃) δ 1.28 (s, 6H), 1.72-1.93 (m, 8H),2.04-2.20 (m, 2H), 3.00 (dd, 1H, J=13.8, 7.6 Hz), 3.23 (dd, 1H, J=13.8,4.7 Hz), 3.28 (m, 1H), 4.07 (dd, 1H, J=12.0, 6.5 Hz), 4.17-4.29 (m, 3H),4.73 (m, 1H), 7.21-7.36 (m, 5H), 11.5 (brs, 1H).

[0729] IR (KBr) 2981, 1718, 1654 cm⁻¹

[0730] TOF-MS: m/z 422 (M⁺+1).

[0731] Elemental Analysis for C₂₄H₃₁N₅O₂.HCl.0.8H₂O

[0732] Calculated(%): C, 61.02; H, 7.17; N, 14.82.

[0733] Found (%): C, 61.09; H, 7.27; N, 14.82.

EXAMPLE 86(R)-8-Benzyl-2-(tert-butyl)-7,8-dihydro-4-(3-hydroxy-3-methylbutyl)-1H-imidazo[2,1-i]purin-5(4H)-onehydrochloride (Compound 86)

[0734] In a manner similar to that in Example 79, a dioxolane compoundwas obtained from Compound 83a obtained in Example 83 and2-(2-bromoethyl)-2-methyl-1,3-dioxolane. Then, the title compound (40mg, 55%) was obtained from the dioxolane compound (90 mg, 0.220 mmol) ina manner similar to that in Example 85.

[0735]¹H-NMR (270 MHz, CDCl₃) δ 1.22 (s, 6H), 1.37 (s, 9H), 1.94 (t, 2H,J=6.4 Hz), 2.86 (dd, 1H, J=13.5, 7.0 Hz), 3.00 (dd, 1H, J=13.5, 6.8 Hz),3.79 (dd, 1H, J=11.3, 6.8 Hz), 4.03 (dd, 1H, J=11.3, 9.7 Hz), 4.23 (t,2H, J=6.4 Hz), 4.41-4.52 (m, 3H), 7.17-7.37 (m, 5H).

[0736] EI-MS: m/z 410 (M⁺+1).

EXAMPLE 87(R)-9-Benzyl-2-ethoxymethyl-6,7,8,9-tetrahydro-4-(n-propyl)-1H-pyrimidino[2,1-i]purin-5(4H)-one(Compound 87)

[0737] In a manner similar to that in Example 45, the title compound (22mg, 18%) was obtained from Compound B12 (95 mg, 0.340 mmol) prepared inReference Example 22 and Compound A12 (90 mg, 0.561 mmol, 1.6equivalents) prepared in Reference Example 11.

[0738]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.4 Hz), 1.24 (t, 3H,J=7.1 Hz), 1.84 (q, 2H, J=7.4 Hz), 1.85 (m, 1H), 2.11 (m, 1H), 2.77 (dd,1H, J=13.7, 7.9 Hz), 2.97 (dd, 1H, J=13.7, 6.6 Hz), 3.64 (q, 2H, J=7.1Hz), 3.77-3.95 (m, 2H), 4.14 (t, 2H, J=7.6 Hz), 4.28 (m, 1H), 4.58 (d,1H, J=11.2 Hz), 4.63 (d, 1H, J=11.2 Hz), 7.17-7.34 (m, 5H).

[0739] EI-MS: m/z 382 (M⁺+1).

EXAMPLE 888-Benzyl-2-ethoxymethyl-6,7,8,9-tetrahydro-4-(n-propyl)-1H-pyrimidino[2,1-i]purin-5(4H)-onefumarate (Compound 88)

[0740] In a manner similar to that in Example 45, the title compound inthe free form was obtained from Compound B12 (200 mg, 0.710 mmol)prepared in Reference Example 22 and Compound A13 (220 mg, 1.33 mmol,1.9 equivalents) prepared in Reference Example 12. The title compound(25 mg, 4%) was obtained as white crystals from the resulting freecompound and fumaric acid.

[0741] Melting point: 152-157° C. (ethyl acetate/n-hexane)

[0742]¹H-NMR (270 MHz, CDCl₃) δ 0.98 (t, 3H, J=7.3 Hz), 1.28 (t, 3H,J=6.9 Hz), 1.81 (q, 2H, J=7.3 Hz), 2.40 (m, 1H), 2.70-2.85 (m, 2H), 3.25(dd, 1H, J=14.2, 9.6 Hz), 3.45 (dd, 1H, J=13.8, 9.9 Hz), 3.66 (dd, 1H,J=14.2, 6.9 Hz), 3.67 (t, 2H, J=6.9 Hz), 4.14 (t, 2H, J=7.4 Hz), 4.44(brd, 1H, J=11.6 Hz), 4.67 (s, 2H), 6.87 (s, 4H), 7.16-7.37 (m, 5H).

[0743] IR (KBr): 1713, 1662, 1605, 1568, 1379, 1362, 1296, 1265, 1111cm⁻¹

[0744] EI-MS: m/z 382 (M⁺+1).

[0745] Elemental Analysis for C₂₁H₂₇N₅O₂.1.0C₄H₄O₄

[0746] Calculated(%): C, 60.35; H, 6.28; N, 14.08.

[0747] Found (%): C, 60.57; H, 6.79; N, 14.12.

EXAMPLE 892-Cyclopentyl-6,7,8,9-tetrahydro-4-(n-propyl)-8-(3-pyridyl)-1H-pyrimidino[2,1i]purin-5(4H)-one (Compound 89)

[0748] In a manner similar to that in Example 45, the title compound (42mg, 12%) was obtained from Compound BI (200 mg, 0.680 mmol) and CompoundA14 (210 mg, 1.40 mmol, 2.0 equivalents) prepared in Reference Example13.

[0749] Melting point: 190-195° C. (acetone/diethyl ether)

[0750]¹H-NMR (270 MHz, CDCl₃) δ 0.97 (t, 3H, J=7.3 Hz), 1.61-1.89 (m,8H), 2.09 (q, 2H, J=7.3 Hz), 3.14-3.30 (m, 2H), 3.51-3.81 (m, 3H),4.04-4.10 (m, 2H), 4.60 (brd, 1H, J=6.9 Hz), 7.32 (dd, 1H, J=7.9, 4.8Hz) 7.55 (brd, 1H, J=7.9 Hz), 8.55-8.59 (m, 2H).

[0751] IR (KBr): 1686, 1645, 1605, 1564, 1504 cm⁻¹

[0752] EI-MS: m/z 379 (M⁺+1).

[0753] Elemental Analysis for C₂₁H₂₆N₆₀.0.3H₂O

[0754] Calculated(%): C, 65.71; H, 6.98; N, 21.89.

[0755] Found (%): C, 65.59; H, 6.91; N, 21.73.

FORMULATION EXAMPLE 1 Tablet

[0756] A tablet having the following formulation is prepared in aconventional manner. Composition Compound 2 20 mg Lactose 143.4 mgPotato starch 30 mg Hydroxypropylcellulose 6 mg Magnesium stearate 0.6mg 200 mg

FORMULATION EXAMPLE 2 Injection

[0757] Injection having the following formulation is prepared in aconventional manner. Composition Compound 9 2 mg Purified soybean oil200 mg Purified yolk lecithin 24 mg Glycerol for injection 50 mgDistilled water for injection 1.72 ml 2.00 ml

TEST EXAMPLE 1 Acute toxicity test

[0758] A test compound was orally administered to dd mice [male, bodyweight: 20±1 g (n=3)]. Mortality rate after seven days was measured todetermine minimum lethal dose (MLD). As a result, MLD of Compound 2 wasnot less than 500 mg/kg (mice, po), which revealed safety of thecompound of the present invention.

TEST EXAMPLE 2 Insulin Secretion Promoting Activity for Cultured β Cells

[0759] The established pancreas β-cell, MIN6 cell, reported by Miyazakiet al. (Endocrinology, vol. 127, pp.126-131, 1990) exhibits insulincontent and insulin secretion amount by stimulation with glucose similarto those of pancreas β-cells in living bodies, and well preservescharacteristics of pancreas β-cells in living bodies from a viewpointthat it shows increase of insulin secretion in a glucoseconcentration-dependent manner (the above reference and Diabetologia,vol. 36, pp.1139-1145, 1993). Further, the insulin secretion of the MIN6cell is promoted in response to sulfonylurea agents such asglibenclamide, which are used as a medicament for treatment of diabetes(Cellular Signalling, vol. 5, pp.777-786, 1993).

[0760] Culture of the MIN6 cells above and insulin secretion testutilizing the MIN6 cells were performed according to the methodsdescribed in Diabetologia, vol. 36, pp.1139-1145, 1993. The effect of acompound on the insulin secretion in the presence of 14.5 mmol/L glucosewas determined by measuring insulin amounts in cell culture supernatantscollected as follows. MIN6 cells cultured on a 24-well plate were washedtwice by using 1 mL of Buffer A (119 mmol/L sodium chloride, 4.74 mmol/Lpotassium chloride, 2.54 mmol/L calcium chloride, 1.19 mmol/L magnesiumsulfate, 1.19 mmol/L potassium dihydrogenphosphate, 10 mmol/L2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, 0.1% bovineserum albumin, pH 7.3) containing 2 mmol/L glucose, and then wereincubated in 1 mL of Buffer A containing 2 mmol/L glucose at 37° C. for45 minutes. After the incubation, the culture supernatant was changed toBuffer A (0.9 mL) containing a test compound at various concentrationsand 2 mmol/L glucose, and the cells were further incubated at 37° C. for15 minutes. The MIN6 cells were stimulated with glucose by the additionof Buffer A (0.1 mL) containing 127 mmol/L glucose to the culture (finalglucose concentration: 14.5 mmol/L). After the stimulation, the cellswere further incubated at 37° C. for 45 minutes, and then the culturesupernatant was collected.

[0761] Separately, the effect of a compound on the insulin secretion inthe presence of 5 mmol/L glucose was determined by measuring insulinamounts in cell culture supernatants collected as follows. MIN6 cellscultured on a 24-well plate were washed twice by using 1 mL of Buffer Acontaining 5 mmol/L glucose, and then the culture supernatant waschanged to Buffer A (0.9 mL) containing a test compound at variousconcentrations and 5 mmol/L glucose. Then, the cells were incubated at37° C. for 45 minutes (final glucose concentration: 5 mmol/L), and theculture supernatant was collected.

[0762] After the culture supernatant was diluted with a phosphate buffercontaining 1% bovine serum albumin, 0.1% Tween 20, 0.12% disodiumethylenediaminetetraacetate (EDTA) and 0.1% sodium azide,antibody-reactive insulin secreted in the culture supernatant wasquantified by enzyme immunoassay or radio immunoassay. The insulin levelwas indicated as the amount of human insulin (ng/mL). The results areindicated as averages (avg) for 3 to 4 samples with standard erroevalues (se).

[0763] The results are shown in Table 2. TABLE 2 (In the presence of14.5 mmol/L of glucose) Drug Insulin secretion amount concentration(ng/ml) Compound No. (μmol/L) avg se None — 148.4 4.8  2 1.0 203.6 13.9 9 1.0 197.6 17.9 10 1.0 196.8 4.6 14 1.0 177.9 2.6 21 1.0 182.1 5.3 241.0 200.0 5.1 40 1.0 191.2 3.1 45 1.0 178.8 8.4 51 1.0 180.8 4.5 56 1.0189.0 3.5 64 1.0 204.9 5.9 70 1.0 174.9 9.6 71 1.0 211.0 1.7 73 1.0176.6 3.9 81 1.0 195.4 7.4 85 1.0 197.1 11.1 AY4166 10 195.1 4.3Glibenclamide 0.1 177.8 3.3 (In the presence of 5 mmol/L of glucose)Drug Insulin secretion amount concentration (ng/ml) Compound No.(mmol/L) avg se None — 51.2 11.3  2 10 86.3 8.2  9 10 74.0 7.6 10 1074.9 3.8 14 10 66.4 2.6 21 10 74.8 5.5 24 10 71.8 8.7 40 10 56.7 2.4 4510 69.9 4.9 51 10 79.2 2.7 56 10 56.2 2.1 64 10 61.2 2.0 70 10 57.0 2.571 10 107.7 9.1 73 10 63.3 2.2 81 10 83.1 2.3 85 10 53.6 1.1 AY-4166 10170.8 4.2 Glibenclamide 0.1 156.8 8.4

[0764] As shown in Table 2, it was revealed that the compounds of thepresent invention had insulin secretion action. Whilst, as shown inTable 2, in the presence of glucose at a low concentration (5 mmol/L),these compounds did not show marked secretion promoting action even at a10 times higher concentration. Glibenclamide (Pharmacotherapy, vol. 5,p.43, 1985) and AY-4166 (Yakuri To Rinsho [Pharmacology and Clinic], vol7, p.121, 1997) used as controls for comparison showed marked secretionpromoting action even at a low glucose concentration.

TEST EXAMPLE 3 Hyperglycemia Suppressing Action After Glucose Loading inNormal Rats

[0765] Wistar male rats (body weight: about 280 g) were used for theexperiment after starvation for 24 hours. A test compound was orallyadministered to the rats 15 minutes before oral administration ofglucose (2 g/kg). Blood was collected from a tail vein before theadministration of the test compound and 30, 60, 120 and 180 minutesafter the glucose loading, and blood glucose level was measured by usinga simplified blood sugar level measuring apparatus.

[0766] The results are shown in Table 3. TABLE 3 Plasma GlucoseConcentration (mg/dl) Dose Compound (mg/kg, po) n 0 30 60 120 180Control — 6 82 ± 3.7 169 ± 7.2  167 ± 8.0 93 ± 4.5 83 ± 3.7 2 14 6 91 ±2.1 144 ± 6.6* 156 ± 5.7 90 ± 5.7 82 ± 4.2

[0767] As clearly shown in Table 3, the compound of the presentinvention was found to have hyperglycemia suppressing action 30 minutesafter the glucose loading. However, the compound exhibited nohypoglycemic action during the fasted state.

INDUSTRIAL APPLICABILITY

[0768] According to the present invention, condensed purine derivatives,which have glucose concentration-dependent insulin secretion promotingaction and hypoglycemic action and are useful as an antidiabetic agentor the like, are provided.

What is claimed is:
 1. A condensed purine derivative represented byFormula (I):

wherein X—Y—Z represents R¹N—C═O (in the formula, R¹ represents ahydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted aromaticheterocyclic group) or N═C—W [in the formula, W represents a halogenatom, a substituted or unsubstituted aromatic heterocyclic group, asubstituted or unsubstituted alicyclic heterocyclic group, —NR⁴R⁵ (inthe formula, R⁴ and R⁵ may be the same or different and each representsa hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aryl group, or a substituted orunsubstituted aralkyl group, or R⁴ and R⁵ may bind to each other to forma heterocyclic group together with the adjacent nitrogen atom), —OR⁶ (inthe formula, R⁶ represents a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted aryl group, or a substituted orunsubstituted aralkyl group), —SR^(6a) (in the formula, R^(6a) has thesame meaning as R⁶ mentioned above), a substituted or unsubstitutedlower alkyl group or a cyano group], R² represents a hydrogen atom, asubstituted or unsubstituted lower alkyl group, a substituted orunsubstituted aralkyl group, a substituted or unsubstituted aryl group,a substituted or unsubstituted aromatic heterocyclic group, asubstituted or unsubstituted alicyclic heterocyclic group, a halogenatom, a lower alkylthio group, —NR⁷R⁸ (in the formula, R⁷ and R⁸ havethe same meanings as R⁴ and R⁵ mentioned above, respectively), —CO₂H, alower alkoxycarbonyl group, —COHal (in the formula, Hal represents ahalogen atom), —CONR⁹R¹⁰ (in the formula, R⁹ and R¹⁰ have the samemeanings as R⁴ and R⁵ mentioned above, respectively) or —CHO, R³represents a hydrogen atom, a lower alkyl group, a substituted orunsubstituted aralkyl group, or a lower alkoxyalkyl group, n representsan integer of from 0 to 3, V¹ represents a hydrogen atom, a substitutedor unsubstituted lower alkyl group, a substituted or unsubstitutedaralkyl group, a substituted or unsubstituted aryl group, or asubstituted or unsubstituted aromatic heterocyclic group, V² representsa substituted lower alkyl group, or a substituted or unsubstitutedaromatic heterocyclic group, and when V¹ represents a hydrogen atom, alower alkyl group, a substituted or unsubstituted aralkyl group, or asubstituted or unsubstituted aryl group, and (a) X—Y—Z representsR^(1a)N—C═O (in the formula, R^(1a) represents any of the groups in thedefinition of the aforementioned R¹ excluding a substituted lower alkylgroup), and R² represents a substituted lower alkyl group, a substitutedor unsubstituted aralkyl group, a substituted or unsubstituted alicyclicheterocyclic group, a halogen atom, a lower alkylthio group, —NR⁷R⁸ (inthe formula, R⁷ and R⁸ have the same meanings as defined above,respectively), —CO²H, a lower alkoxycarbonyl group, —COHal (in theformula, Hal has the same meaning as defined above), —CONR⁹R¹⁰ (in theformula, R⁹ and R¹⁰ have the same meanings as those defined above,respectively) or —CHO, (b) X—Y—Z represents R¹N—C═O (in the formula, R¹has the same meaning as defined above), and R³ represents a loweralkoxyalkyl group, (c) X—Y—Z represents R^(1b)N—C═O (in the formula,R^(1b) represents a substituted lower alkyl group), (d) X—Y—Z representsN═C—W (in the formula, W has the same meaning as defined above), and R²represents a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted aromaticheterocyclic group, a substituted or unsubstituted alicyclicheterocyclic group, a halogen atom, a lower alkylthio group, —NR⁷R⁸ (inthe formula, R⁷ and R⁸ have the same meanings as defined above,respectively), —CO²H, a lower alkoxycarbonyl group, —COHal (in theformula, Hal has the same meaning as defined above), —CONR⁹R¹⁰ (in theformula, R⁹ and R¹⁰ have the same meanings as defined above,respectively) or —CHO, or (e) X—Y—Z represents N═C—W (in the formula, Whas the same meaning as defined above), and R³ represents a lower alkylgroup, a substituted or unsubstituted aralkyl group, or a loweralkoxyalkyl group, V² may represent a lower alkyl group, a substitutedor unsubstituted aralkyl group, or a substituted or unsubstituted arylgroup; or a pharmacologically acceptable salt thereof.
 2. The condensedpurine derivative or a pharmacologically acceptable salt thereofaccording to claim 1, wherein X—Y—Z represents R¹N—C═O (in the formula,R¹ has the same meaning as defined above).
 3. The condensed purinederivative or a pharmacologically acceptable salt thereof according toclaim 2, wherein R¹ and R² each represents a substituted orunsubstituted lower alkyl group and R³ represents a hydrogen atom. 4.The condensed purine derivative or a pharmacologically acceptable saltthereof according to claim 2 or claim 3, wherein at least one of V¹ andV² represents a substituted lower alkyl group.
 5. The condensed purinederivative or a pharmacologically acceptable salt thereof according toclaim 2 or claim 3, wherein at least one of V¹ and V² represents asubstituted or unsubstituted aralkyl group.
 6. The condensed purinederivative or a pharmacologically acceptable salt thereof according toclaim 1, wherein X—Y—Z represents N═C—W (in the formula, W has the samemeaning as defined above).
 7. The condensed purine derivative or apharmacologically acceptable salt thereof according to claim 6, whereinR² represents a substituted or unsubstituted lower alkyl group.
 8. Thecondensed purine derivative or a pharmacologically acceptable saltthereof according to claim 6 or claim 7, wherein at least one of V¹ andV² represents a substituted or unsubstituted aralkyl group.
 9. Thecondensed purine derivative or a pharmacologically acceptable saltthereof according to any one of claims 1 to 8, wherein n is
 0. 10. Apharmaceutical composition which comprises the condensed purinederivative or a pharmacologically acceptable salt thereof according toany one of claims 1 to 9 as an active ingredient.
 11. An agent forprophylactic and/or therapeutic treatment of diabetes, which comprisesthe condensed purine derivative or a pharmacologically acceptable saltthereof according to any one of claims 1 to 9 as an active ingredient.12. An agent for prophylactic and/or therapeutic treatment of acomplication of diabetes which comprises the condensed purine derivativeor a pharmacologically acceptable salt thereof according to any one ofclaims 1 to 9 as an active ingredient.
 13. A hypoglycemic agent whichcomprises the condensed purine derivative or a pharmacologicallyacceptable salt thereof according to any one of claims 1 to 9 as anactive ingredient.
 14. An insulin secretion promoter which comprises thecondensed purine derivative or a pharmacologically acceptable saltthereof according to any one of claims 1 to 9 as an active ingredient.15. Use of the condensed purine derivative or a pharmacologicallyacceptable salt thereof according to any one of claims 1 to 9 for themanufacture of a pharmaceutical composition.
 16. Use of the condensedpurine derivative or a pharmacologically acceptable salt thereofaccording to any one of claims 1 to 9 for the manufacture of an agentfor prophylactic and/or therapeutic treatment of diabetes.
 17. Use ofthe condensed purine derivative or a pharmacologically acceptable saltthereof according to any one of claims 1 to 9 for the manufacture of anagent for prophylactic and/or therapeutic treatment of a complication ofdiabetes.
 18. Use of the condensed purine derivative or apharmacologically acceptable salt thereof according to any one of claims1 to 9 for the manufacture of a hypoglycemic agent.
 19. Use of thecondensed purine derivative or a pharmacologically acceptable saltthereof according to any one of claims 1 to 9 for the manufacture of aninsulin secretion promoter.
 20. A method for prophylactic and/ortherapeutic treatment of diabetes, which comprises a step ofadministering an effective amount of the condensed purine derivative ora pharmacologically acceptable salt thereof according to any one ofclaims 1 to
 9. 21. A method for prophylactic and/or therapeutictreatment of a complication of diabetes mellitus, which comprises a stepof administering an effective amount of the condensed purine derivativeor a pharmacologically acceptable salt thereof according to any one ofclaims 1 to
 9. 22. A method for decreasing blood sugar level, whichcomprises a step of administering an effective amount of the condensedpurine derivative or a pharmacologically acceptable salt thereofaccording to any one of claims 1 to
 9. 23. A method for promotinginsulin secretion, which comprises a step of administering an effectiveamount of the condensed purine derivative or a pharmacologicallyacceptable salt thereof according to any one of claims 1 to 9.